Ciba Vision Symposium: 16th Symposium, Osaka-tokyo, November 2003 Proceedings (Ophthalmologica Vol 218 Supplement 1)

Lecture 1: Presentation of the Speaker

Risk Profiles for Ageing Macular Disease

Speaker

Prof. Paulus T.V.M. de Jong, MD, PhD Netherlands Ophthalmic Research Institute

Chairmen

ABC Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Prof. Dr. Yoshihisa Oguchi

Prof. Dr. Akira Negi

Keio University School of Medicine

Kobe University Medical School

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Lecture 1: Presentation of the Speaker

Curriculum vitae Paulus T.V.M. de Jong Netherlands Ophthalmic Research Institute, KNAW, Amsterdam, the Netherlands

Date of birth: September 12, 1942 Place of birth: Heerlen, the Netherlands Nationality: The Netherlands Marital status: Married, two children Education/Degrees: 1961 Latin school, Heerlen 1961–1967 Medical school, University of Utrecht 1967–1969 Internships, University Hospital Utrecht 1969 (September 5) MD, University of Utrecht 1973 (February 8) PhD thesis in neuroscience, University of Amsterdam Compulsory Military Service: 1969–1971 Lieutenant Royal Navy as an MD Certification: 1969 (February 12) ECFMG, certificate No. 094 800 0 1969 (September 5) General practitioner’s licence 1975 (August 1) Netherlands Register of Ophthalmologists 1989 (February 10) Fellow Royal College of Ophthalmologists, London (FRCOphth) 1997 (November 11) Licensed to perform animal experiments (Art. 9, Law on Animal Experiments) 2001 (May 5) Fellow European Board of Ophthalmology (FEBO)

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Academic and Governmental Appointments: 1967–1973 Part-time neuroscience researcher, Experimental Laboratory, Ear Nose Throat Department, University of Amsterdam 1973–1982 Senior lecturer, University of Amsterdam 1982–1995 Professor and chair of ophthalmology, Erasmus University, Rotterdam (EUR) 1982–1988 Extraordinary professor of ophthalmology, the Netherlands Ophthalmic Research Institute (NORI), Amsterdam 1989– Principal investigator, ophthalmic part of the Rotterdam Study, EUR 1995–2002 Director, NORI of the Royal Netherlands Academy of Arts and Sciences 1995– Staff member, Department of Epidemiology and Biostatistics, EUR 1999– Professor of ophthalmic epidemiology, EUR 2002– Senior investigator, NORI Hospital Appointments: 1971–1975 Resident in ophthalmology, University of Amsterdam 1973–1974 Three and 2 months’ locum as ophthalmic surgeon in Jalalpur Jattan, Pakistan 1975–1982 Staff ophthalmologist, University Hospital, University of Amsterdam 1982–1992 Staff ophthalmologist, Eye Hospital, Rotterdam 1992–1995 Chair, Department of Ophthalmology, University Hospital Dijkzigt, Rotterdam 1996 Staff ophthalmologist, University Hospital Amsterdam, AMC

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Editorial Board Membership: 1999– Investigative Ophthalmology and Visual Science 1995– Survey of Ophthalmology Former (Board) Memberships: European Organization for Research and Treatment of Cancer, Ophthalmic Oncology Group (founder) Lasers and Light in Ophthalmology (1993–1999) Nederlands Tijdschrift voor Geneeskunde (1990–1995) The Netherlands Melanoma Group of the Cancer Foundation KWF The Netherlands Society for Medical Education Honours: Umbra Erasmi, EUR, the Netherlands

Lecture 1: Presentation of the Speaker

Memberships: Applied Vision Association Association for Research in Vision and Ophthalmology Association for Eye Research Club Jules-Gonin Fellow European Board of Ophthalmology Fellow Royal College of Ophthalmologists, London International Ergophthalmological Society (chair 1990– 2000) International Fluorescein Angiography Club International Perimetric Society International Society of Geographical and Epidemiological Ophthalmology International Society for Genetic Eye Diseases Julius-Hirschberg-Gesellschaft (board member) Macula Society The Netherlands Biophysics Society The Netherlands Ergophthalmological Committee The Netherlands Fluorescein Angiography Club The Netherlands Society for the Prevention of Blindness (vice-chairman) Ophthalmological Societies of Belgium, France, Germany, Greece, the Netherlands, the UK and the USA

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Lecture 1 Ophthalmologica 2004;218(suppl 1):8–16 DOI: 10.1159/000079462

Risk Profiles for Ageing Macular Disease Paulus T.V.M. de Jong a, b, c a Department

of Ophthalmogenetics, Netherlands Ophthalmic Research Institute, KNAW, b Department of Ophthalmology, Academic Medical Centre, Amsterdam, and c Department of Epidemiology and Biostatistics, Erasmus University, Rotterdam, The Netherlands

Ageing macular disease (AMD) is now the most common cause of incurable blindness and visual impairment in the Western world above the age of 55 years [1], and it is encouraging that the interest for this disorder is increasing. A quick count in PubMed resulted in 7 publications on AMD in 1971 and 516 in 2002. We have, however, no proof and only some inkling what the pathogenesis of AMD is, and thus its prophylaxis or prevention is hardly possible. Of late, several risk factors of AMD became known, and the purpose of this paper is to update you on the most important ones. First I will discuss the stages of AMD followed by its natural course, incidence, risk factors, and risk profiles for individual subjects; I will end with some future developments. This paper is a reflection of lectures in which the emphasis was put on AMD especially with regard to the Rotterdam Study (RS), and thus it should not be considered to be a complete review of the risk profiles for AMD. Many data will be derived from the RS, a population-based study on diseases in subjects aged 55 years and over [2]. For those unfamiliar with epidemiology it can be stated that as a rule of thumb prevalence studies cannot really demonstrate causal relationships and that good population-based incidence studies of sufficient size are more likely to provide true risk factors than similar case-control or trial studies.

Definitions

degenerating or have a degenerative disorder, Alan Bird proposed to change degeneration for disease. Because ageing better indicates older age than age-related (c.f. juvenile macular disease is also age related), I prefer the term ‘ageing macular disease’. It is essentially a combination of the term ‘senile macular degeneration’ as first described by Haab in 1885 [3] that we now would call dry, geographic or atrophic AMD, and ‘disciform degeneration’ as described by Junius and Kuhnt in 1926 [4] now also called wet or neovascular AMD. Thus, I will deviate from the International Classification System for ARM and AMD [5] (ICSAMD) in so far that all ARM will now be called AMD, and I will thus speak of early and late AMD. This ICSAMD [5] does not incorporate visual acuity in its definition. It divides early AMD according to drusen type, size, number, area of retina they cover and retinal pigment epithelial hypopigmentations and hyperpigmentations. Late AMD denotes the earlier mentioned geographic atrophic and disciform forms. The ICSAMD will have to be updated, if only because it comprises over 50 different (combinations of) signs of AMD and because at the time of its conception little was known about the predictive power of these individual signs with regard to acquiring late AMD. That is why we classified for the purpose of defining incident AMD (iAMD) the various fundus signs of early AMD in mutually exclusive stages, each stage having a higher risk of late AMD than the previous ones.

With the disease AMD, I mean the same as age-related macular degeneration (AMD) or age-related maculopathy (ARM). Because patients do not like to hear that they are

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Accessible online at: www.karger.com/oph

Paulus T.V.M. de Jong Department of Ophthalmogenetics, Netherlands Ophthalmic Research Institute Meibergdreef 47 NL–1105 BA Amsterdam (The Netherlands) Tel. +31 20 566 4588, Fax +31 20 566 9050, E-Mail [email protected]

Table 1. Mutually exclusive stages of early and late AMD progressively predicting late AMD

Stages

Definitions

0

a b

No signs of AMD at all Hard drusen (! 63 Ìm) only

1

a b

Soft distinct drusen (663 Ìm) only Pigmentary abnormalities only, no soft drusen

2

a

Soft indistinct drusen (6125 Ìm) or only reticular drusen Soft distinct drusen (663 Ìm) with pigmentary abnormalities

b 3

Soft indistinct (6125 Ìm) or reticular drusen with pigmentary abnormalities

4

Atrophic or neovascular AMD (= late AMD) From Klaver et al. [6].

Table 2. Estimated 5-year risk (%) of visual

acuity (VA) loss ! 0.1 due to late AMD according to AMD stage AMD stage, VA ! 0.1

%

0 1 2 3 4 atrophic AMD 4 neovascular AMD

0.1 1.1 8.5 26.3 25 26

Fig. 1. Classification of AMD stages for incidence studies [6, 7].

Percentages given for stages 4 refer to fellow eye.

Stages

stages of late AMD. Nevertheless when looking at the risk of visual acuity loss in pooled data from eyes with various AMD stages, on average the risk of acuity loss !0.1 is inversely related to the stage of AMD (table 2).

In table 1 and figure 1, the stages are given of the pooled fundus signs of early and late AMD. On each fundus transparency, a grid was positioned, centered on the fovea, and the graders marked if fundus signs were present within or outside the grid. It is evident that visual acuity cannot play a role in the definition of AMD not only because AMD is a disease defined by exclusion of other ones (e.g. disciform reaction due to presumed ocular histoplasmosis or high myopia), but also because one can have normal visual acuity even in the beginning

The prevalence of AMD (cross-sectional number of cases at baseline) is given in figure 2 [6, 7]. It is clear that the various AMD stages are age dependent. As mentioned, incidence data are more reliable for finding risk factors of a disease than prevalence data. Incidence is the number of new cases of a disease within a certain time span. The 2-year cumulative incidence (all new cases in 2

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Ophthalmologica 2004;218(suppl 1):8–16

Natural Course and Incidence of AMD

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Fig. 2. Prevalence of various stages of AMD in the RS according to

age strata.

Table 3. Incidence rates of stages of AMD per 1,000 person-years based on a 2-year follow-up (2-year cumulative incidence)

Baseline stage of AMD

Person years

0 1 2 3

638.99 936.85 498.34 103.74

Stage of AMD at follow-up 1

2

3

4

136.2 (24) 3.1 (1) 0 0 139.8 (24) 10.7 (2) 0 148.5 (26) 14.0 (3) 48.2 (9)

The 2-year cumulative incidence, expressed as a percentage, is shown in parentheses [6].

Fig. 3. Five-year risk (%) of late iAMD as a function of age and AMD stage at baseline [7].

years) of AMD is seen in table 3 [6], which shows that about one quarter of all participants move in 2 years from one stage to the next. Only eyes with stage 3 seemed to be at a lower risk of progressing to stage 4. As definition of iAMD we used the absence of a fundus sign specific for a certain stage of AMD within the grid area in either eye and the presence of a sign in a higher stage in at least 1 eye at follow-up [7]. The 5-year absolute risks of stage 4 AMD as a function of stage and age at baseline are given in figure 3 and table 4a [7]. This seems to me an important table because for the first time I feel that we have data telling the ophthalmologist what exactly the risk for her/his patient with early AMD is to get end-

Table 4a. Five-year absolute risk (%) of late AMD as a function of stage of early AMD and age

at baseline

Stage of ARM

Baseline fundus sign of AMD

OR

95% CI

Total drusen area 1 10% of grid Presence of depigmentation Presence of hyperpigmentation 610 small drusen (^63 Ìm) 610% drusen confluence

5.7 4.0 3.4 2.5 2.5

2.9–11.3 2.5–6.4 2.1–5.4 1.5–4.1 1.7–3.8

0 1 2 3 Total

10

Age group 60–69 years

70–79 years

680 years

total

0.0 0.5 3.0 17.5

0.1 1.1 9.2 22.5

0.0 2.4 11.9 42.0

0.0 0.9 7.8 28.0

0.2

1.3

3.3

0.9

Ophthalmologica 2004;218(suppl 1):8–16

Table 4b. Odds ratios (OR) for late iAMD according to fundus signs

CI = Confidence interval. Definitions of the AMD stages are presented in table 1 [6, 7].

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Fig. 4. Odds ratio of iAMD according to ankle-arm index (AAI).

Fig. 5. Relative risk of iAMD associated with carotid artery wall

Based on a model which included these factors, and age, baseline stage of AMD and duration of follow-up period.

thickness analyzed in tertiles.

stage AMD, according to stage of AMD and age of the patient. Also individual fundus signs are predictive of late (stage 4) AMD (table 4b).

the bottom line is that for normal ageing there seems at present not to be a widely acclaimed cure. There is a wealth of theories why ageing has a deleterious effect on AMD. With increasing age we find thickening and calcification of Bruch’s membrane in the retina, lipid deposition in it, impaired transport of nutrients across this membrane, and loss of capillary density and impaired blood flow in the choriocapillaris. Basal laminar deposits around the retinal pigment epithelium increase, eventually leading to ophthalmoscopically discernable drusen.

Risk Factors

There are excellent reviews on risk factors of AMD [8– 12]. I divided these factors in incurable and possibly curable ones. Among the former I reckon alphabetically age, (subclinical) atherosclerosis, other cardiovascular disorders of which hypertension is an exception with regard to cure, family history of AMD, genetics and gender, highdensity lipoprotein (HDL) hypercholesterolemia, hyperopia, inflammation and race (Caucasian vs. black and perhaps Japanese race). The possibly curable ones are antioxidant (micronutrient) deficiency, high or low body mass index (BMI), specific medicine use, early menopause and perhaps estrogen deficiency, as well as smoking. I will subsequently discuss those risk factors that we studied more extensively in the RS.

Incurable Factors Age From all prevalence and incidence studies, it is clear that age is strongly associated with AMD. It goes too far to discuss here the cause of or a possible cure for ageing, but

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Subclinical Atherosclerosis The most commonly used measures for subclinical atherosclerosis are the blood pressures taken at the ankle divided by those in the arm, the so-called ankle/arm index, calcified plaques in the aorta on abdominal X-rays and carotid artery intima-media thickness and calcifications, determined by ultrasonography. An ankle/arm index !0.9 is indicative of generalized atherosclerosis. Dividing the population at risk for iAMD in tertiles and taking the highest tertile as reference we found that subjects with the lowest ankle/arm index had an odds ratio (OR) of 1.32–1.39 depending on adjustments for various risk factors (fig. 4) [12a]. The significance disappeared only after adjusting for blood pressure, also a risk factor for atherosclerosis. Carotid wall intima-media thickness is one of the best markers for atherosclerosis. Also here the highest tertile had the highest risk of iAMD (fig. 5, table 5).

Ophthalmologica 2004;218(suppl 1):8–16

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Table 5. OR of iAMD related to carotid artery wall thickness and plaques

Adjusted OR

Number of

Wall thickness of carotid artery per SD increase Wall thickness of carotid artery 1st tertile 2nd tertile 3rd tertile Plaques in carotid artery per extra plaque Categories of plaques in carotid artery 0 1–3 4–6

subjects

cases

model 1

model 2

model 3

4,020

349

1.16 (1.04, 1.29)

1.17 (1.04, 1.31)

1.13 (1.00, 1.27)

1,479 1,369 1,172 3,237

92 123 134 286

1.00 1.27 (0.95, 1.70) 1.51 (1.11, 2.04) 1.06 (0.98, 1.15)

1.00 1.34 (0.99, 1.80) 1.60 (1.16, 2.20) 1.06 (0.98, 1.15)

1.00 1.29 (0.95, 1.74) 1.47 (1.06, 2.05) 1.04 (0.96, 1.13)

1,372 1,423 442

106 125 55

1.00 1.02 (0.77, 1.35) 1.46 (1.02, 2.10)

1.00 1.02 (0.77, 1.36) 1.50 (1.03, 2.19)

1.00 0.97 (0.73, 1.30) 1.37 (0.94, 2.01)

Figures in parentheses indicate 95% confidence intervals. Model 1: adjusted for age and gender; model 2: additional adjustment for smoking, total and HDL cholesterol, BMI and diabetes mellitus; model 3: additional adjustment for systolic and diastolic blood pressure. From van Leeuwen et al. [12a].

Cardiovascular Risk Factors Of the cardiovascular risk factors other than atherosclerosis only elevated blood pressure seems to lead to iAMD. Per 10 mm Hg rise in systolic blood pressure, the OR was 1.07 (95% confidence interval, CI, 1.01–1.13), and above 160 mm Hg the OR for iAMD was 2.08 (95% CI 1.36–3.20). Hyperglycemia seems not to have a high impact on incident AMD [53]. Family History of AMD Family history of diseases often seems to be unreliable. However, when ascertained in case of AMD there definitely is a higher lifetime risk for both early AMD (2.1; 95% CI 1.4–3.1) and an even higher risk (4.2; 95% CI 2.6–6.8) for late AMD in first-degree relatives [13]. Genetics and Gender Only over the last 10 years has it gradually emerged that AMD is a multifactorial disorder having both genetic and environmental components in its pathogenesis. By means of a nested case-control study in AMD cases and controls in the RS, we found a population-attributable genetic risk of AMD of 27% [13]. So far only 3 genes have been identified (ABCR4, the paraoxonase gene and APOE gene), accounting for an estimated 10% of all AMD cases. Women seem to be at a slightly higher risk of AMD according to a meta-analytical study [9] but other studies than the RS could not confirm this [14].

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HDL Hypercholesterolemia To our surprise, HDL hypercholesterolemia was found to be a risk factor for iAMD [15]. Per standard deviation increase in serum HDL cholesterol, the OR for iAMD was 1.20 (95% CI 1.06–1.35). This finding should be confirmed by other studies, and I would not advise at this moment to lower high HDL cholesterol levels as they seem protective to many cardiovascular disorders. The influence of fat metabolism and AMD is a complicated one, especially when one also takes into account the apolipoprotein  (APO Â) influence on this. The association between HDL cholesterol and iAMD was stronger in persons having the APO Â4 allele. At present we do not know, however, why having the APO Â4 polymorphism carries a lower risk of AMD and a higher risk of Alzheimer’s disease while for APO Â2 the opposite holds. Hyperopia That hyperopia is a risk factor for AMD has been mentioned since 1979 [16] and was confirmed in several casecontrol studies [17–20]. One population-based study found a slightly enhanced risk [21], another a slightly protective effect only for early AMD [22]. When we analyzed the relationship between hyperopia and AMD, we found for each diopter spherical equivalent towards hyperopia an OR of 1.09 both for early and for late prevalent AMD (pAMD) [23]. Eyes with myopia lower than –3 dpt had a nonsignificant lower OR for pAMD of 0.64, eyes with hyperopia 1+3 dpt had a significant OR of pAMD of 1.46

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Table 6. OR of AMD according to spherical equivalents (SphE) of refraction SphE (continuous)

Advanced myopia versus emmetropia

Myopia versus emmetropia

Hyperopia versus emmetropia

Advanced hyperopia versus emmetropia

pAMD at baseline pAMD (n = 536) Early pAMD (n = 440) pAMD (n = 96)

1.09 (1.04–1.13) 1.09 (1.04–1.14) 1.09 (1.00–1.19)

0.64 (0.38–1.09) 0.67 (0.37–1.20) 0.61 (0.20–1.89)

1.21 (0.83–1.74) 1.37 (0.92–2.05) 0.71 (0.31–1.64)

1.18 (0.89–1.58) 1.32 (0.96–1.82) 0.87 (0.47–1.59)

1.46 (1.05–2.04) 1.62 (1.12–2.34) 1.14 (0.57–2.24)

Early iAMD iAMD (n = 497)

1.05 (1.01–1.10)

0.69 (0.43–1.11)

0.79 (0.53–1.16)

1.09 (0.82–1.43)

1.20 (0.85–1.69)

Figures in parentheses indicate 95% CI. Refraction: adjusted for age, gender (and follow-up time); range: in pAMD, –18.75 to +15.13 dpt; in iAMD, –18.75 to +9.63 dpt; relative risk per diopter towards hyperopia. Advanced myopia: SphE ^ –3.0 dpt; myopia: –3.0 dpt ! SphE ^ –0.5 dpt; emmetropia: –0.5 dpt ! SphE ! +0.5 dpt; hyperopia: +0.5 dpt ^ SphE ! +3.0 dpt; advanced hyperopia: SphE 6 +3.0 dpt. From Ikram et al. [23].

(table 6) [23]. Also per diopter towards hyperopia the OR for iAMD was 1.05 (table 6). What exactly determines why myopia is protective against AMD is uncertain. We hypothesized that it might be circulatory due to a thicker choroid or throttling of the vorticose veins by a thicker sclera. Inflammation Inflammation has incidentally been referred to as a cause of AMD. Interest in macrophages, seen in pathology slides already over 10–15 years ago, has resurged, partly by finding drusen and AMD signs in mice deficient in monocyte chemoattractant protein 1 (CCL-2; also known as MCP-1) or its cognate CC chemokine receptor 2 (CCR2) [24]. Inflammation seems also to be involved in atherosclerosis. Recent publications support the inflammatory hypothesis showing immune deposits in drusen [25, 26] and a trend between C-reactive protein and AMD [27]. How high this risk is, if it is a reflection of local or generalized disease, and what the cause is of these inflammation markers still has to be established.

sayama Study [29]. Blacks were mostly reported to have a lower prevalence of AMD, but later reports suggested that this holds only for late AMD [30, 31]. This same pattern seems to exist in Mexican Americans who have similar rates to those of Caucasians for early AMD but possibly have lower ones for late AMD [32, 33]. One should be aware that the life expectancy of the Mexican Americans is lower and these studies looked at younger age cohorts. I am not aware of Japanese population-based epidemiological studies with comparable sizes and techniques that enable a valid comparison with prevalences or incidences of AMD in other races.

Possibly Curable Factors

Race It seems that various population-based studies in Caucasians found different prevalence rates for AMD, and this may partly be explained by differences in examination techniques and diagnostic criteria. Most studies give prevalences for early plus late AMD between the ages of 70 and 80 years between 25 and 40%. Only the RS [14] and the Blue Mountain Study in Australia [28] reported prevalences between 10 and 20%, as did the smaller Hi-

Dietary Antioxidants Also data on dietary antioxidant deficiency have been controversial with regard to their effect on iAMD. In casecontrol and population-based studies low vitamin A [34], E [35], serum carotenoids [36] and lutein [37] were found to be associated with an increased risk of AMD while other studies found no associations [38]. A trial study with very high doses of vitamin C and E, ß-carotene and zinc showed a protective effect for late AMD [39]. We looked at the effect of dietary intake of these carotenoids and micronutrients on iAMD and found indeed that ·- and ß-carotene, vitamin C and E, and zinc intake in a higher than average proportion had a definite protective effect on iAMD (data submitted). This seems to be the first time since the description of AMD that a beneficial effect of a

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healthy but normal diet without any supplements has been described. Body Mass Index Several papers found that a higher BMI was a risk factor of AMD [40, 41]. On the other hand, also low BMI has been involved in AMD [42], or no association was found [43]. We will still have to look at BMI at baseline and the risk of iAMD to try to solve this controversy. Medicine Use In case specific diseases are associated with a higher risk of AMD, it is to be expected that also drug treatment of such diseases shows higher associations, apart from the fact whether this is due to the disease or to the drug. One should be aware of confounding by indication. Thus we found in the RS a spurious higher association between AMD and the use of a specific vasodilator because in the past one ophthalmologist in that area prescribed this drug to all his late AMD cases ‘in order to make them believe that something could be done for them’. Another problem in medicine association studies is that most studies recorded at baseline what drugs a subject was using but had no idea for how long a period before or after that moment. In the RS, we found cross-sectionally no significant associations between pAMD and the use of ACE inhibitors, antithrombotic drugs, ß-blockers, calcium channel blockers, cardiac glycosides, diuretics, estrogen replacement therapy, NSAIDs, steroid hormones or vitamin supplementations. There, however, was a direct association between lipid-lowering drugs, including cholesterol synthesis inhibitors, synthetic thyroid hormones and pAMD. In a pooled 3-continent study, no strong associations between medication use and early iAMD were found apart from a possible increased risk with ß-blocker use and a protective effect of hormone replacement therapy and tricyclic antidepressants [44]. We could not confirm in the RS a protective effect of cholesterol-lowering drugs on iAMD either by calculating the cumulative use of these drugs [45]. Early Menopause or Estrogen Deficiency Early menopause can occur due to special syndromes or to surgical procedures resulting in loss of ovarian function. The latter was shown in one report from the RS to be associated with prevalent AMD [46]. Estrogens protect among others against atherosclerosis, and thus it is not sure if this is an epiphenomenon or a direct effect of estrogen loss. A logical consequence would be to look at the effect of estrogen hormonal replacement therapy. In the

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Ophthalmologica 2004;218(suppl 1):8–16

RS, the number of women at baseline to use this therapy was too small to study its possible effects but in the pooled findings from the Beaver Dam, Blue Mountains and RS we found a slightly protective effect [44]. Other studies on hormone replacement therapy have been inconclusive. Smoking After the first mention of deleterious effects of smoking on AMD [47], this has been confirmed in numerous reports [17, 48–52]. With ORs around 2.5, smoking is one of the most consistently found modifiable risk factors for AMD. More and more mechanisms why smoking may be deleterious become apparent, but most still have to be confirmed. It may be some consolation for smokers that stopping smoking seems to reduce the risk of AMD [49, 51].

Risk Profiles for Individual Persons

Most of my AMD patients, when offered the choice to hear what their visual prognosis is, want to be fully informed also with regard to current therapies. Thanks to several (population-based) incidence studies we have made much progress in the last decade compared to the previous century in defining the natural course of AMD, and we can now relatively well predict one’s chance of getting late AMD (table 4). The more of the previously mentioned risk factors one can add to this table, the more the need arises to modify the curable ones, especially because the first possibilities of prevention by healthy food or supplements became available. I personally feel happier advising supplementation in case of dietary insufficiency after our findings that corroborated the AREDS trial results that vitamins C and E, ß-carotene and zinc have a protective effect on AMD. Information about reducing the risk of AMD (apart from many other disorders) may create an extra impetus for smokers and obese people to change their lifestyle.

Future Developments

The future for patients with early AMD looks much brighter than 5 years ago. We not only have a tool for moderate prevention, we have better proof of risk factors that can be modified. For geographic atrophy, no cures have been developed yet. For neovascular AMD, the downhill course can be modified by photodynamic therapy. New promising therapies with antivascular endothelial growth factors and corticosteroid derivates are on their way. More and more research groups are concentrat-

de Jong

ing on finding new genes associated with AMD, hopefully leading to better prevention and therapeutic strategies. In short, I feel that the ophthalmic community is catching up fast with regard to helping their AMD patients compared to its seemingly indifference in the past.

Acknowledgements These lectures were only made possible due to the help of my former PhD students Caroline C.W. Klaver, Mike Kliffen, Redmer van Leeuwen and Johannes R. Vingerling, of the AMD graders Ada Hooghart and Corina Brussee and the Board of the ROOS Foundation, all in Rotterdam, the Netherlands.

References 1 Klaver CCW, Wolfs RCW, Vingerling JR, Hofman A, De Jong PTVM: Age-specific prevalence and causes of blindness and visual impairment in an older population. Arch Ophthalmol 1998;116:653–658. 2 Hofman A, Grobbee DE, de Jong PTVM, van den Ouweland FA: Determinants of disease and disability in the elderly: The Rotterdam elderly study. Eur J Epidemiol 1991;7:403– 422. 3 Haab O: Erkrankungen der Macula lutea. Zentralbl Prakt Augenheilkd 1885;9:383–384. 4 Junius P, Kuhnt H: Die scheibenförmige Entartung der Netzhautmitte (Disciform degeneration of the retinal centre). Berlin, Karger, 1926. 5 The international ARM epidemiological study group, Bird AC, Bressler NM, Bressler SB, Chisholm IH, Coscas G, Davis MD, de Jong PTVM, Klaver CCW, Klein BEK, Klein R, Mitchell P, Sarks JP, Sarks SH, Soubrane G, Taylor H, Vingerling JR: An international classification and grading system for age-related maculopathy and age-related macular degeneration. Surv Ophthalmol 1995;39:367–374. 6 Klaver CCW, Assink JJM, Van Leeuwen R, Wolfs RCW, Vingerling JR, Stijnen T, Hofman A, de Jong PTVM: Incidence and progression rates of age-related maculopathy: The Rotterdam Study. Invest Ophthalmol Vis Sci 2001; 42:2237–2241. 7 van Leeuwen R, Klaver CCW, Vingerling JR, Hofman A, de Jong PTVM: The risk and natural course of age-related maculopathy: Followup at 6½ years in the Rotterdam Study. Arch Ophthalmol 2003;121:519–526. 8 Vingerling JR, Klaver CCW, Hofman A, de Jong PTVM: Epidemiology of age-related maculopathy. Epidemiol Rev 1995;17:347–360. 9 Evans JR: Risk factors for age-related macular degeneration. Prog Retin Eye Res 2001;20: 227–253. 10 Van Leeuwen R, Klaver CCW, Vingerling JR, Hofman A, de Jong PTVM: Epidemiology of age-related maculopathy: A review. Eur J Epidemiol 2003;18:845–854. 11 Zarbin MA: Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 2004;122:598–614. 12 Klein R, Peto T, Bird AC, Vannewkirk MR: The epidemiology of age-related macular degeneration. Am J Ophthalmol. 2004;137:486– 495. 12a Van Leeuwen R, Ikram MK, Vingerling JR, Witteman JCM, Hofman A, de Jong PTVM: Blood pressure, atherosclerosis, and the inci-

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dence of age-related maculopathy: The Rotterdam Study. Invest Ophthalmol Vis Sci 2003; 44:3771–3777. Klaver CCW, Wolfs RCW, Assink JJM, van Duijn CM, Hofman A, de Jong PTVM: Genetic risk of age-related maculopathy. Arch Ophthalmol 1998;16:1646–1651. Vingerling JR, Dielemans I, Hofman A, Grobbee DE, Hijmering M, Kramer CFL, de Jong PTVM: The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 1995;102:205–210. Van Leeuwen R, Klaver CCW, Vingerling JR, Hofman A, Stricker BHC, Van Duijn CM, de Jong PTVM: Cholesterol and age-related maculopathy: Is there a link? Am J Ophthalmol 2004;137:750–752. Maltzman BA, Mulhivil MN, Greenbaum A: Senile macular degeneration and risk factors: A case-control study. Ann Ophthalmol 1979;11: 1197–1201. Hyman LG, Lilienfeld AM, Ferris FL 3rd, Fine SL: Senile macular degeneration: A case-control study. Am J Epidemiol 1983;118:213– 227. Weiter JJ, Delori FC, Wing GL, Fitch KA: Relationship of senile macular degeneration to ocular pigmentation. Am J Ophthalmol 1985; 99:185–187. Eye Disease Case Control Study Group: Risk factors for neovascular age-related macular degeneration. Arch Ophthalmol 1992;110:1701– 1708. Sandberg MA, Tolentino MJ, Miller S, Berson EL, Gaudio AR: Hyperopia and neovascularization in age-related macular degeneration. Ophthalmology 1993;100:1009–1013. Wang JJ, Mitchell P, Smith W: Refractive error and age-related maculopathy: The Blue Mountains Eye Study. Invest Ophthalmol Vis Sci 1998;39:2167–2171. Klein R, Klein BEK, Jensen SC, Cruickshanks KJ: The relationship of ocular factors to the incidence and progression of age-related maculopathy. Arch Ophthalmol 1998;116:506–513. Ikram MK, van Leeuwen R, Vingerling JR, Hofman A, De Jong PTVM: Relationship between refraction and prevalent as well as incident age-related maculopathy: The Rotterdam Study. IOVS 2003;44:3778–3782. Ambati J, Anand A, Fernandez S, Sakurai E, Lynn BC, Kuziel WA, Rollins BJ, Ambati BK: An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nat Med 2003;11:1390–1397.

25 Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF: An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001;20:705–732. 26 Crabb JW, Miyagi M, Gu X, Shadrach K, West KA, Sakaguchi H, Kamei M, Hasan A, Yan L, Rayborn ME, Salomon RG, Hollyfield JG: Drusen proteome analysis: An approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci USA 2002;99:14682– 14687. 27 Seddon JM, Gensler G, Milton RC, Klein ML, Rifai N: Association between C-reactive protein and age-related macular degeneration. JAMA 2004;291:704–710. 28 Mitchell RA: Prevalence of age related macular degeneration in persons aged 50 years and over resident in Australia. J Epidemiol Community Health 1993;47:42–45. 29 Miyazaki M, Nakamura H, Kubo M, Kiyohara Y, Oshima Y, Ishibashi T, Nose Y: Risk factors for age related maculopathy in a Japanese population: The Hisayama study. Br J Ophthalmol 2003;87:469–472. 30 Schachat AP, et al: Features of age-related macular degeneration in a black population: The Barbados Eye Study Group. Arch Ophthalmol 1995;113:728–735. 31 Klein R, et al: Prevalence of age-related maculopathy in the Atherosclerosis Risk in Communities Study. Arch Ophthalmol 1999;117: 1203–1210. 32 Cruickshanks KJ, et al: The prevalence of agerelated maculopathy by geographic region and ethnicity: The Colorado-Wisconsin Study of Age-Related Maculopathy. Arch Ophthalmol 1997;115:242–250. 33 Klein R, Rowland ML, Harris MI: Racial/ethnic differences in age-related maculopathy. Third National Health and Nutrition Examination Survey. Ophthalmology 1995;102:371– 381. 34 Goldberg J, Flowerdew G, Smith E, Brody JA, Tso MO: Factors associated with age-related macular degeneration: An analysis of data from the first National Health and Nutrition Examination Survey. Am J Epidemiol 1988;128:700– 710. 35 West SK, Vitale S, Hallfrisch J, Munoz B, Muller D, Bressler S, Bressler NM: Are antioxidants or supplements protective for age-related macular degeneration? Arch Ophthalmol 1994; 112:222–227.

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36 Eye Disease Case-Control Study Group: Antioxidant status and neovascular age-related macular degeneration. Arch Ophthalmol 1993; 111:104–109. 37 Seddon JM, Ajani UA, Sperduto RD, Hiller R, Blair N, Burton TC, Farber MD, Gragoudas ES, Haller J, Miller DT, et al: Dietary carotenoids, vitamins A, C, and E, and advanced agerelated macular degeneration. Eye Disease Case-Control Study Group. JAMA 1994;272: 1413–1420. 38 Mares-Perlman JA, Klein R, Klein BE, Greger JL, Brady WE, Palta M, Ritter LL: Association of zinc and antioxidant nutrients with agerelated maculopathy. Arch Ophthalmol 1996; 114:991–997. 39 Age-Related Eye Disease Study Research Group: A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report No 8. Arch Ophthalmol 2001;119:1417–1436. 40 Klein R, Klein BE, Franke T: The relationship of cardiovascular disease and its risk factors to age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology 1993;100:406–414.

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41 Hirvela H, et al: Risk factors of age-related maculopathy in a population 70 years of age or older. Ophthalmology 1996;103:871–877. 42 Smith W, et al: Plasma fibrinogen levels, other cardiovascular risk factors, and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol 1998;116:583–587. 43 Smith W, et al: Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology 2001;108: 697–704. 44 Van Leeuwen R, Tomany SC, Wang JJ, Klein R, Mitchell P, Hofman A, Klein BEK, Vingerling JR, Cumming RG, de Jong PTVM: Is medication use associated with the incidence of early age-related maculopathy? Pooled findings from three continents. Ophthalmology 2004; 111:1169–1175. 45 Van Leeuwen R, Vingerling JR, Hofman A, de Jong PTVM, Stricker BHC: Cholesterol lowering medication and risk of age related maculopathy: Prospective cohort study with cumulative exposure measurement. BMJ 2003;326: 255–256. 46 Vingerling JR, Witteman J, Dielemans I, Hofman A, Grobbee DE, de Jong PTVM: Macular degeneration and early menopause: A case control study. Br Med J 1995;310:1570–1571.

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47 Paetkau ME, Boyd TA, Grace M, Bach-Mills J, Winship B: Senile disciform macular degeneration and smoking. Can J Ophthalmol 1978;13: 67–71. 48 Vinding T, Appleyard M, Nyboe J, Jensen G: Risk factor analysis for atrophic and exudative age-related macular degeneration: An epidemiological study of 1,000 aged individuals. Acta Ophthalmol (Copenh) 1992;70:66–72. 49 Vingerling JR, et al: Age-related macular degeneration and smoking: The Rotterdam Study. Arch Ophthalmol 1996;114:1193– 1196. 50 Smith W, Mitchell P, Leeder SR: Smoking and age-related maculopathy: The Blue Mountains Eye Study. Arch Ophthalmol 1996;114:1518– 1523. 51 Delcourt C, et al: Smoking and age-related macular degeneration: The POLA Study. Pathologies oculaires liées à l’âge. Arch Ophthalmol 1998;116:1031–1035. 52 McCarty CA, Mukesh BN, Fu CL, Mitchell P, Wang JJ, Taylor HR: Risk factors for age-related maculopathy: The Visual Impairment Project. Arch Ophthalmol 2001;119:1455–1462.

de Jong

Lecture 2: Presentation of the Speaker

Pathogenesis of Diabetic Retinopathy and Strategy to Develop New Therapeutic Modalities

Speaker

Prof. Dr. Hidetoshi Yamashita Yamagata University School of Medicine

Chairmen

ABC Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Dr. Koji Kurata

Prof. Dr. Yozo Miyake

Chairman of the Tokyo Association of Ophthalmologists

Nagoya University School of Medicine

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Lecture 2: Presentation of the Speaker

Curriculum vitae Hidetoshi Yamashita Department of Ophthalmology and Visual Science, Yamagata University School of Medicine, Yamagata, Japan

Education: 1981 MD degree: University of Tokyo Faculty of Medicine 1986 PhD degree: University of Tokyo

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Postgraduate appointments: 1981–1982 Resident of the Department of Ophthalmology, University of Tokyo Faculty of Medicine 1982–1985 Research Associate of the Department of Ophthalmology, University of Tokyo Faculty of Medicine 1985–1987 Department of Ophthalmology, Mishuku Hospital (Tokyo) 1987–1999 Assistant Professor, Department of Ophthalmology, University of Tokyo Faculty of Medicine 1992–1994 Postdoctoral fellow, Ludwig Institute for Cancer Research, Biomedical Center, Uppsala University, Sweden From 1999 Professor of Ophthalmology and Visual Science, Yamagata University School of Medicine

Yamashita

Lecture 2 Ophthalmologica 2004;218(suppl 1):19–28 DOI: 10.1159/000079463

Pathogenesis of Diabetic Retinopathy and Strategy to Develop New Therapeutic Modalities Hidetoshi Yamashita Department of Ophthalmology and Visual Science, Yamagata University School of Medicine, Yamagata, Japan

Thank you Dr. Kurata for the kind introduction. I am really glad to be able to speak on this splendid occasion. I appreciate the efforts made by all the members of the executive committee. Now, I am going to talk about diabetic retinopathy. I am afraid that my talk cannot cover the standard views of this disease, but I want to share with you the way my colleagues and I have been tackling the problems of diabetic retinopathy.

Increase in Patients with Diabetes

Many of us are aware of the recent marked increase in diabetes patients, but it is difficult to provide quantitative evidence of this increase. The Ministry of Health, Labor and Welfare, Japan, has been conducting National Nutrition Surveys every 5 years. An interim summary of the latest data for 2002 was presented in August 2003. When we compare the data for 1997 and 2002, we find that the number of persons strongly suspected to have diabetes increased from 6,900,000 to 7,400,000 – more than a 5% increase in the last few years. The number of potential diabetics has increased from 13,700,000 to 16,200,000 (fig. 1). A dramatic increase has also been shown on a longer time scale, but we cannot rely on the accuracy of longterm comparison because there have been changes in the diagnostic criteria for diabetes. An index available for long-term comparison is the population-based prevalence calculated from the number

ABC

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Fig. 1

of persons visiting medical institutions. As compared with the data for 1955, the prevalence of patients who visited medical institutions and were diagnosed as having diabetes has increased by about 30 times during the last 40 years. This increase coincided with the rapid economic growth of Japan. There have been a number of factors contributing to this increase, such as lack of exercise due to the widespread use of cars and reorganization of the nation’s industrial structure. A very important factor has been the change in the pattern of food consumption. In particular, there has been a drastic increase in the intake

Prof. Hidetoshi Yamashita Department of Ophthalmology and Visual Science Yamagata University School of Medicine Yamagata 990-9585 (Japan) Tel. +81 23 628 5374, Fax +81 23 628 5376, E-Mail [email protected]

Fig. 2

of animal fat. Fat consumption has increased from 7% to over 20% during the last 40 years. The National Nutrition Survey for 2002 revealed another important fact. These data show increases in diabetes in the different age groups. While diabetes has been increasing among the aged persons, the data also show an alarming increase in potential diabetics among young people. Because these individuals are likely to develop overt diabetes sometime in the future, this increase presents a serious problem (fig. 2). The increase in the number of diabetics is anticipated to continue. It is very difficult to estimate the prevalence of diabetic retinopathy at present. We can assume that roughly 30% of the 7 million diabetics in Japan have retinopathy. The data shown here from a hospital-based study need some downward correction, but 30% seem to be a good figure for population studies. This assumption indicates that there are more than 2 million patients with diabetic retinopathy at present in Japan. Thus, the occurrence of diabetic retinopathy is quite high, although it is less prevalent than glaucoma, which affects 4 million people and is another important cause of blindness in Japan. As Professor Oguchi said, diabetic retinopathy is the number 1 leading cause of blindness in Japan. Although it is second to glaucoma in some districts, we can definitely say that glaucoma and diabetes are serious problems. An important issue of concern is the spread of diabetes among young people, which seems to be ongoing and accelerating. Less than half of the diabetic patients visiting the outpatient clinic of Yamagata University retain a visual acui-

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ty of 0.7. This may be due to the fact that diabetic patients without retinopathy represent a smaller percentage of the diabetic patients visiting university hospitals than those of a population-based survey. A visual acuity of less than 0.7 is a serious problem for people because they cannot keep a driver’s license. How good then is the vision of average Japanese elderly people who are not diabetics? We conducted a population-based survey on the aged citizens of Sagae City, Yamagata Prefecture – a city renowned for its cherries. We examined about 70 persons out of the 100 persons 70 years of age living in the area and found that about 90% of them retained a visual acuity of 0.7 or better. This figure seems to reflect the very high level of ophthalmological care in Japan. A person at the age of 70 usually retains a visual acuity of 0.7 or better, which is sufficient for most daily life and work activities. However, this holds true only for people without diabetes. The presence or absence of diabetes is strongly related to not only blindness but also a visual acuity decrease and the quality of vision in daily life. The patients with progression to proliferative retinopathy naturally have poorer vision than those without progression. The treatments for proliferative retinopathy, including surgery and photocoagulation, rarely achieve recovery to a visual acuity of 0.7 or better. Because the number of people with diabetes is increasing, the number of people with retinopathy is also expected to increase. Thanks to progress in treatment methods, the incidence of blindness has become much lower than it was decades ago. Nowadays, we are facing the need for preserving better visual acuity for the whole life. How then can we overcome these problems of diabetic retinopathy? I want to discuss two different strategies.

Pathological Study on Diabetic Retinopathy

One is the very macroscopic approach of constructing a system of medical care, including health screening. The other is the development of new therapies and new drugs. In both approaches, we want to see what we can do for each patient in cooperation with physicians in internal medicine before photocoagulation is needed. According to the current diagnostic criteria, a patient is considered to have diabetes if he shows a fasting blood sugar of 126 mg/dl or higher, or a 2-hour oral glucose tolerance test of 200 mg/dl or higher. The evidence behind these criteria is the fact that diabetic retinopathy, nephropathy and microvascular complications increase dramatically when the patient exceeds either of these values as the threshold.

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Fig. 3

Fig. 4

These criteria are set at the levels at which the occurrence of retinopathy is very low. Thus, the diagnosis of diabetes can be established before the onset of complications, in particular the first minimal vascular complications. We do not want a situation in which the patient has already developed retinopathy when he is first diagnosed as having diabetes. The diagnostic criteria represent a line between tolerable conditions and the disease state. A condition called impaired glucose tolerance (IGT) occurs just below this line (fig. 3). (Note that macroangiopathy develops in a somewhat different manner.) Individuals with IGT are potential diabetic patients in a condition between normal blood glucose and diabetes. These individuals, in particular those with high 2-hour oral glucose tolerance test values who are not diabetic but show moderately elevated blood glucose after meals, are reported to have a high probability of developing diabetes (fig. 3). In view of the aforementioned increase in diabetic patients, we should first try to limit the number of diabetic patients to limit the number of those with retinopathy. This strategy is attracting much attention from physicians in internal medicine. An answer in this direction was given by the Diabetes Prevention Program in the USA. This program attempted to prevent progression from IGT to diabetes. Large numbers of subjects, about 1,000 subjects in each group, were assigned to 3 protocols: no intervention, medication and lifestyle. The lifestyle improvement group was instructed to lose weight, keep physically active for a minimum of 150 min daily and follow a low-fat diet. The subjects were followed up for about 3 years. The results confirmed that the lifestyle improvement strongly suppressed the development of diabetes. While individuals with IGT develop

diabetes at a probability of about 10% per year, improvement of lifestyle, such as exercise and limitation of fat intake, decreased this probability by more than half (fig. 4) [1]. The USA are expanding this approach to a community level and striving to curb the increase in diabetes by social insurance activities. Currently, we have a Japanese version of the Diabetes Prevention Program in progress. We ophthalmologists are very interested in what we should do after a patient has developed diabetes. We want to know who is likely to develop diabetic retinopathy and correctly evaluate the risks for developing retinopathy. In this respect, we have found that diabetes in Japanese is basically similar to that in western people. When comparing the results from two studies on type 2 diabetes, conducted by the Japan Diabetes Complication Study (JDCS) and by the UK Prospective Diabetes Study, many background factors were similar between these two studies. Concerning the body mass index, however, a large difference can be seen. While diabetic patients were not always obese in Japan, in western countries diabetic patients are obese (fig. 5) [2]. According to Dr. Chikako Ito, a famous internal medicine physician, diabetic patients in the USA mainly die from cardiovascular diseases, in particular heart diseases. On the other hand, Japanese diabetic patients die due to cerebrovascular diseases and nephropathy in addition to heart diseases. There seems to be a slight difference in the profile of diabetic complications between Japanese and western populations. A survey by the Ministry of Health and Welfare (now Ministry of Health, Labor and Welfare) indicated that the

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Fig. 5

Fig. 6

prevalence of retinopathy increased with the duration of type 2 diabetes. The prevalence was 30–40% among patients who had been ill for 10 years and 80% among those with a duration of 20 years. The Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR) in the USA also indicated a prevalence of 30–40 or 40–50% after 10 years of diabetes and 80% after 20 years. The results were similar to those in Japan (fig. 6) [3]. The JDCS is now being continued under the leadership of the principal investigator, Prof. Nobuhiro Yamada, Department of Internal Medicine, University of Tsukuba, supported by a team investigation program of the Ministry of Health, Labor and Welfare. About 2,200 subjects at 59 medical institutions have been followed up for several years. The incidence of retinopathy among Japanese patients with type 2 diabetes is about 20% per 5 years. About 4– 5% of the patients without retinopathy develop diabetic retinopathy every year. The statistical data from other countries basically fall within a similar range. There is little difference among countries with respect to the occurrence of retinopathy (fig. 7) [4–7]. The most important risk factor for retinopathy among these patients is poor blood sugar control. According to the JDCS, a 1% increase in hemoglobin A1c is associated with an increase in retinopathy by a factor of 1.4. Blood pressure and the duration of diabetes have also been identified as risk factors. The effect of hemoglobin A1c was also examined in the Wisconsin study. The odds ratios, found to fall to the 1.2–1.4 range, were similar to those in Japan (fig. 8) [8].

The progression from mild nonproliferative retinopathy to severe nonproliferative or proliferative retinopathy occurs at a rate of about 10% per 5 years, or 2% per year. The data from other countries indicate a similar risk profile (fig. 9) [9, 10]. High levels of hemoglobin A1c were associated with a marked progression of retinopathy, and the magnitude of the effect shows little difference between the JDCS in Japan and WESDR in the USA. In this sense, diabetic retinopathy in Japan does not differ much from that in western and Caucasian populations. While macroangiopathy, retinopathy and other complications show measurable differences, retinopathy does not differ much among different populations. We do not know how much genetic background is related to the development of retinopathy, but I suspect that it may be much less than we previously assumed. As a matter of fact, retinopathies in western and Japanese populations resemble each other with respect to the risk profile. We now understand that hyperglycemia significantly contributes to the development of retinopathy in various ways (fig. 10).

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Treatment Strategies

There have been no large-scale intervention studies conducted in Japan, but we have data from the Diabetes Complication and Control Trial in the USA, as well as the UK Prospective Diabetes Study in the UK. Let’s look at the results of the former, which provided very clear-cut data. In this study, a group of patients with type 1 insulindependent diabetes was treated with conventional thera-

Yamashita

Fig. 7

Fig. 9

Fig. 8

Fig. 10

py, while another group was given intensive insulin therapy to suppress the postprandial blood glucose increase and to lower the average of the blood glucose level. During the early phase of the study, the high blood sugar group and the low blood sugar group showed a considerable difference in the incidence of retinopathy. It was significantly lower in the group of conventional insulin therapy than in the intensive insulin therapy. This result is very reasonable (fig. 11, taken from the lecture of Prof. D. Nathan) [11a, b]. The problem is the results of the later phase of the study. At one point, the regimens were switched, and the two groups were given the same treatment. The patients who had previously had high blood sugar came to have low blood sugar after the switch of

regimens. Other patients maintained low blood sugar levels from the beginning to the end. Even when the two groups had the same level of blood sugar, the difference in the risk for retinopathy incidence continued to increase. The patients with good blood sugar control by the intensive therapy from the beginning remained at low risk, but those who switched from the conventional therapy to good blood sugar control by the intensive therapy continued to be affected by their past risk level. Prof. D. Nathan, who was involved in this study, proposed the concept of ‘imprinting’ in the lecture at the International Diabetes Federation congress in Paris in 2003 [11]. The effects of initial blood sugar control persist for at least several years. It is very important to identify

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Fig. 11

Fig. 12

diabetes and start intensive therapy as soon as possible (fig. 11). This coincides with the rationale for the aforementioned diagnostic criteria. We need to identify patients before the onset of retinopathy and treat them. Population-based screening must hold the answer to this problem (fig. 11). We have not come up with a decisive methodology as yet, but I want to introduce a study in Funagata Town, Yamagata Prefecture. This study in the field of internal medicine has become well recognized both in Japan and internationally. The study was led by Prof. Makoto Tominaga, Department of Clinical Diagnosis on Biology and Hormonal Regulation, Yamagata University, Faculty of Medicine, and I participated in it for a time after I had moved to the present post at Yamagata University Faculty of Medicine. We conducted very intensive examinations of diabetic patients in Funagata town at intervals of 5 years to evaluate the incidence of new diabetes cases and the prevalence of potential diabetic patients, i.e. individuals who are liable to develop diabetes, in the population. While the study showed a recent increase in diabetes, it also showed an alarming increase in potential diabetic patients. This coincided with the aforementioned result of the national survey. Because we examined all inhabitants at 5-year intervals, every newly diagnosed case was considered to have been ill for less than 5 years. The prevalence of retinopathy among these individuals was about 6%, twice that among other individuals. The good news was that the retinopathy detected in these people was very slight with almost no bleeding. This means that we succeeded in early detection. It may be advisable to increase the frequency of examination. Although additional efforts

and better methods and systemization would be required, diabetes examination and diagnosis conducted at least once every few years would improve the detection of new cases and facilitate early treatment. I want to emphasize again the importance of blood sugar control. Next, let’s consider how we can develop new therapies. On the macroscopic level, the most important factor is hyperglycemia. Study of the pathological processes stemming from hyperglycemia has just provided us with a clear view of what is happening on the molecular level. The challenge is to identify which observation is the most important. Hyperglycemia, of course, means elevated glucose concentration. Glucose is a substance having a number of functional groups and is active in various chemical reactions. It binds to various proteins and triggers many intracellular signal transduction systems. Among various factors in these systems, much attention has recently been directed to oxidative stress (fig. 12). This diagram (fig. 13) was taken from the review article in Diabetes Care by Dr. A. Ceriello and the special lecture given by Dr. M. Brownlee [13] at the International Diabetes Federation congress in August 2003. Oxidative stress occurs in the upstream portion of metabolic abnormalities, and we can block various metabolic errors by suppressing this oxidative stress. We studied a source of oxidative stress and evaluated the cell damage due to it. It was very high in proliferative retinopathy, and we considered oxidative stress to at least be involved in clinical cases. Though nitrogen monoxide (NO) works in complicated ways, we examined NO as a factor causing oxidative stress. In diabetic retinopathy, blood vessel damage and

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Yamashita

Fig. 13

the resulting retinal ischemia enhance the production of enzymes producing many reactive oxygen species. It damages the retina, impairs cells and modifies proteins (fig. 13). Naturally, living tissues have a protective mechanism against such actions. In retinal cells, a number of processes have been found to involve the reduced form of glutathione. When oxidative stress is applied, the reduced form of glutathione is consumed, and the oxidized components are reduced to their original forms. There is a recycling system in the retina to prevent depletion of the reduced form of glutathione. The oxidized form of glutathione is returned to its reduced form by an enzyme, and it is again used to process the products of oxidative stress. Thus, there are cycles of reactions driven by 2 enzymes: glutathione reductase and glutathione peroxidase 1 (fig. 14) [14–16]. In the development of the retina, both these enzymes are expressed before the retina is completely formed. The data shown here are from rat eyes. In mice, eyelid opening takes place and the eyes begin to move about 2 weeks postnatally. By this time, the retina has been completed beautifully, and the expression of both glutathione reductase and peroxidase 1 has been enhanced. At the same time, the enzyme synthesizing NO is also enhanced. This seems to have some physiological significance (fig. 15) [14–16]. By the way, when NO is produced in living tissues, it is produced from L-arginine by an enzyme called NO synthase (NOS). There are 3 isoforms of NOS. In the retina, only neuronal NOS and endothelial NOS are normally expressed. Inducible NOS (iNOS) is expressed only in response to stimulation by ischemia, cytokines etc. During the process of embryogenesis, iNOS is expressed in the

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Fig. 14

Fig. 15

retina, in particular the visual cell layer of the inner layer. This probably has physiological significance. It seems not to act simply as an oxidative agent, but to have some physiological function (fig. 16, 17) [12, 17]. When the retina is put under ischemic conditions, very high levels of iNOS and other enzymes are induced in the inner nuclear layer. The data suggest a very strong enhancement of NO generation in this area. NO is the primary cause of oxidative stress, and it oxidizes various substances. While the antioxidative activity of living tissues requires consumption of the reduced form of glutathione, NO actually acts on the enzyme recycling glutathione and blocks it. Because NO acts on both sides of the system, it causes very severe impairment. Although NO

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Fig. 16

Fig. 18

Fig. 17

has some physiological roles, an excess of NO is known to be harmful in many ways. Now, we can look for drugs against diabetic oxidative stress. The substances shaded in green in figure 17 are drugs that have been approved for use under other indications [12] (modified). The use of these drugs for this purpose is not covered by national health insurance, but we can prescribe them legally and they are relatively effective in suppressing oxidative stress. These are good candidates for future therapeutic agents. In addition to the system involving glutathione, there are other systems quenching active oxygen species. One of the candidates is catalase. Copious release of various cytokines takes place downstream from oxidative stress. One such cytokine is vascu-

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lar endothelial growth factor (VEGF), which causes neovascularization. A small amount of VEGF is present in the normal retina in the vicinity of blood vessels of the inner layer. In an experimental rat model, the expression of VEGF was enhanced remarkably in all parts of the retina even when there was no obstruction of blood vessels. Dr. Funatsu of Tokyo Women’s Medical College observed very high levels of VEGF associated with the progression of retinopathy. In this figure, VEGF levels are plotted on a logarithmic scale. VEGF increased by 10- to 100-fold as compared to the baseline level (fig. 18) [18]. Animal experiments also showed that several cytokines play roles in diabetes models. Naturally, these are considered to function as part of a network. Recently, attention has been directed to angiotensin II, which is reportedly increased in proliferative retinopathy [19]. Dr. Funatsu demonstrated the angiotensin II increase to parallel the VEGF increase. This result agrees with various in vitro data. Angiotensin II has been found to induce VEGF in several types of cells. It seems to act in cooperation with VEGF, and it has been reported to occur in the retina (fig. 19, 20) [20]. Angiotensin II occurs not only in the eye but also in blood. It seems probable that a considerable amount of angiotensin II leaks from blood and enters the eye. On the contrary, we may be able to use angiotensin antagonists for therapeutic purposes, if we can limit systemic effects. In fact, a drug suppressing this pathway has been introduced in the clinical treatment for hypertension. In the case of nephropathy, the effectiveness of such an approach has been tested in the Losartan study. The results have been published. Because the report was accepted by

Yamashita

Fig. 19

Fig. 20

the New England Journal of Medicine, a very high-level journal, I think the results are credible. This approach is expected to be useful for the treatment of retinopathy. In truth, there are both positive and negative reports on the efficacy of these agents. This is a problem that ophthalmologists need to solve in the future. We have found that hyperglycemia triggers several cascades and results in the activation of various substances. However, this knowledge is based on studies examining whether known factors are increased or decreased. We also need to examine what is taking place in the eyes without preconceptions. We need to examine systematically and exhaustively which factors are increased and what the causes of those increases are. A new methodology for such a study is proteome analysis. Dr. Tanaka, a 2002 Nobel laureate in chemistry, laid the foundation for this methodology. In this study, the fluid in the eye was taken and examined. Vitreous samples from eyes with a macular hole were used as the normal control, as they were considered to represent a condition similar to normal eyes. Normal vitreous humor contains a number of proteins. In the eye with proliferative retinopathy, both the quantities and types of proteins are dramatically increased. All proteins occurring in the eye with a macular hole are present in the eye with proliferative retinopathy. It seems that proliferative retinopathy is a result of the addition of several proteins to the basic state of the eye with a macular hole. Most of the additional proteins are derived from serum, and a great many of them are related to inflammation. Cathepsin D is an enzyme that decomposes proteins. This seems to suggest the presence of inflammation and decomposition of something (fig. 21) [21].

IL-6 and other inflammation-related factors also increase in the eye. Dr. Teiko Yamamoto (Toho University, presently at Yamagata University) examined the eyes after surgery for diabetic macular edema without proliferative retinopathy and confirmed the elevated levels of IL6 after membrane removal. Thus, IL-6 and other factors seem to be involved in various stages. In view of the suspected involvement of inflammation, it is natural that steroids are effective, but this is kind of an afterthought. Recently, administration of steroids around or into the eye has been reported to be effective. We also tried this treatment and confirmed excellent efficacy. After all, drugs to suppress inflammation were found to be useful in diabetes (fig. 22) [22].

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Fig. 21

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living tissues. Because a factor like this is working in living tissues, there would appear to be antioxidative activity, as indicated by proteome analysis. Although this is all we have at present, I expect to see new therapeutic agents emerging in the future. I am delighted to be able to conduct very interesting studies with so many excellent coworkers. Thank you very much for your attention.

Fig. 22

Another interesting factor is catalase. The level of catalase is known to be extremely high in the eye with proliferative retinopathy. This enzyme has an antioxidative property and seems to be involved in the self-healing ability of

Joint Research Persons Toho University: Prof. S. Takeuchi; Hiroshima University: Prof. H. Mishima, Assistant Prof. A. Minamoto, Dr. Y. Tsumamoto, Dr. K. Yamane; Tokyo Women’s Medical University: Prof. S. Hori, Prof. S. Kitano, Dr. H. Funatsu; Yamagata University: Prof. M. Tominaga, Prof. K. Goto, Prof. J. Fujii, Assistant Prof. M. Igarashi; Mitsubishi Chemical BCL: Dr. T. Yamashita, Dr. S. Taki; University of Tsukuba: Prof. N. Yamada, JDC Study Group; Yamagata University (Department of Ophthalmology and Visual Science): Assistant Prof. (associate member) T. Yamamoto, Dr. I. Onuma, Dr. R. Kawasaki, Dr. H. Sato, Dr. K. Saito, Dr. T. Sato.

References 1 Knowler WC, Barrett-Connor E, Fowler SE, et al: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403. 2 Sone H, Ito H, Ohashi Y, et al: Obesity and type 2 diabetes in Japanese patients. Lancet 2003;361:85. 3 Klein R, Klein BE, Moss SE, et al: The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 1984;102:527–532. 4 Ohkubo Y, Kishikawa H, Araki E, et al: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6year study. Diabetes Res Clinc Pract 1995;28: 103–117. 5 Leske MC, Wu S-Y, Hennis A, et al: Incidence of diabetic retinopathy in the Barbados Eye Studies. Ophthamology 2003;110:941–947. 6 Funatsu H, Hori S, Yamashita H: Rate of progression of diabetes retinopathy. Jpn Rev Clin Ophthalmol 1993;87:976–982. 7 Nakagami T, Kawahara R, Hori S, et al: Effect of diabetic control on the development of retinopathy in non-insulin dependent diabetes mellitus. J Japan Diab Soc 1996;39:901–906. 8 Klein R, Klein BE, Moss E, et al: Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA 1988;260: 2864–2871.

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9 Klein BEK, Davis MD, Segal P, et al: Diabetic retinopathy. Assessment of severity and progression. Ophthalmology 1984;91:10–17. 10 Garg SK, Marshall G, Chase HP, et al: The use of the Markov process in describing the natural course of diabetic retinopathy. Arch Ophthalmol 1990;108:1245–1247. 11 Nathan D: 10 years after the DCCT: From DCCT to EDIC and beyond. International Diabetes Federation Congress, Paris, August 2003. 11a Nathan D: The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986. 11bNathan D: DCCT/EDIC Research Group: Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000;342:381– 389. 12 Ceriello A: New insights on oxidative stress and diabetic complications may lead to a ‘causal’ antioxidant therapy. Diabetes Care 2003; 26:1589–1596. 13 Brownlee M: Biochemistry and Molecular Cell Biology of Diabetic Complications. International Diabetes Federation Congress, Paris, August 2003. 14 Yamashita H, Horie K, Yamamoto T, et al: Superoxide dismutase in developing mouse retina. Jpn J Ophthalmol 1994;38:148–161.

Ophthalmologica 2004;218(suppl 1):19–28

15 Fujii T, Mori K, Takahashi Y, et al: Immunohistochemical study of glutathione reductase in rat ocular tissues at different developmental stages. Histochem J 2001;33:267–272. 16 Fujii T, Ikeda Y, Yamashita H, et al: Transient elevation of glutathione peroxidase 1 around the time of eyelid opening in the neonatal rat. J Ocul Pharmacol Ther 2003;19:361–369. 17 De La Cruz P, Arrebola M, Gonzalez-Correa A, et al: Effects of clopidogrel and ticlopidine on experimental diabetic ischemic retinopathy in rats. Naunyn-Schmiedeberg’s Arch Pharmacol 2003;367:204–210. 18 Funatsu H, Yamashita H, Noma H, et al: Stimulation and inhibition of angiogenesis in diabetic retinopathy. Jpn J Ophthalmol 2001;45: 577–584. 19 Sato S, Katagiri Y, Goto K: Immunohistochemical observation of diacylglycerol kinase in normal and the early stage of diabetic rat. ARVO Meeting, USA, 2003. 20 Funatsu H, Yamashita H, Nakanishi Y, et al: Angiotensin II and vascular endothelial growth factor in the vitreous fluid of patients with proliferative diabetic retinopathy. Br J Ophthalmol 2002;86:311–315. 21 Yamane K, Minamoto A, Yamashita H, et al: Proteome analysis of human vitreous proteins. Mol Cell Proteomics 2003;2:1177–1187. 22 Saitoh K, Sato H, Kawasaki R: Posterior subtenon’s jnjection of triamcinolon acetonide for macular edema. Folia Ophthalmol Jpn 2004; 55:100–104.

Yamashita

Lecture 3: Presentation of the Speaker

Therapeutic and Cosmetic Indications of Lotrafilcon A Silicone Hydrogel Extended-Wear Lenses

Speaker

Dr. René G. Mély Saarlouis, Germany

Chairmen

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Prof. Dr. Mitsuru Sawa

Prof. Dr. Shigeru Kinoshita

Nihon University School of Medicine

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29

Lecture 3: Presentation of the Speaker

Curriculum vitae René G. Mély Louis Pasteur University, Strasbourg, France

Date of birth: March 1, 1956 Nationality: French Medical school: Louis Pasteur University, Strasbourg, France

1

2 Academic and Employment History: 1974–1981 Medical School in Strasbourg, France 1981–1986 Registrar in anesthesia to Dr. Sauerwein and Dr. Altmeyer at the Department of Anesthesia in Saarbrücken, Germany 1986–1987 Specialist (anesthetist) at the Department of Anesthesia in Saarbrücken, Germany June 26, 1986 Medical doctor (Doctorat d’Etat en Médecine) at the University of Strasbourg, France 1987–1991 Registrar in ophthalmology to Prof. Schlegel and Prof. Ruprecht at the Department of Ophthalmology of the Saarland University, Germany Head of the Contact Lens Department 1990–1991 February 21, 1992 Registration as ophthalmologist (Saarland Medical Council, Germany) From 1993 Ophthalmologist in own private practice in Saarlouis, Germany From 1994 to 2000 Co-editor of the international medical contact lens journal Contactologia (Enke-Verlag, Stuttgart, Germany) From 2000 German delegate at the Section of Ophthalmology of the European Union of Medical Specialists From 2000 Chairman of the Publication Committee of the International Medical Contact Lens Symposium 2002 as part of the 29th International Congress of Ophthalmology in Sydney From 2003 Secretary general of the European Contact Lens Society of Ophthalmologists (ECLSO) (elected September 2002)

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3 4 5 6

7

8

Publications: Mély R: Le traitement chirurgical de la diverticulose colique compliquée – A propos de 125 observations. Thèse, Strasbourg, 1986, No 174. Mély R: Einmallinsen – Derzeitiger Stand und Perspektiven. Augenärztl Fortbild 1994;17:82–84. Mély R: Kontaktlinsen für verlängerte Tragezeit. Augenärztl Fortbild 1994;17:120–122. Mély R: Die Anpassung weicher Kontaktlinsen. Augenärztl Fortbild 1994;17:61–64. Mély R: Lentilles à usage unique et à remplacement fréquent en Allemagne. Contactologia 1996;18:31–35. Mély R: Management of myopic anisometropic amblyopia with contact lenses in children. Contactologia 1998;20:165–169. Mély R: Extended Wear von Kontaktlinsen im historischen Vergleich: Wohin führt der Weg? Ophthalmol Nachrichten 2001;5(DOC-Kongressausgabe 1):18. Mély R: Kontaktlinsen ausschliesslich in augenärztlicher Verantwortung: Therapie mit Silikonhydrogellinsen. Ophthalmol Nachrichten 2002;6(DOC-Kongressausgabe 1):18–19.

Mély

Invited Talks: 1991, January 26 Homburg/Saar, Germany 1st Contact Lens Course of the University Eye Clinic of Homburg/Saar (1) Fitting Soft Contact Lenses; (2) Extended-Wear Lenses 1992, January 25 Homburg/Saar, Germany 2nd Contact Lens Course of the University Eye Clinic of Homburg/Saar (1) Fitting Soft Contact Lenses; (2) Extended-Wear and Disposable Lenses 1993, January 23 Homburg/Saar, Germany 3rd Contact Lens Course of the University Eye Clinic of Homburg/Saar (1) Fitting Soft Contact Lenses; (2) Extended-Wear and Disposable Lenses 1994, January 22 Homburg/Saar, Germany 4th Contact Lens Course of the University Eye Clinic of Homburg/Saar Extended-Wear and Disposable Lenses 1994 Neubrandenburg, Germany 1. Wissenschaftliches BVA-Kontaktlinsen-Kolloquium Neubrandenburg Fitting Soft Contact Lenses 1995, January 28 Homburg/Saar, Germany 5th Contact Lens Course of the University Eye Clinic of Homburg/Saar (1) Disposable and Frequent-Replacement Lenses; (2) Fitting Soft Contact Lenses; (3) Extended-Wear and Disposable Lenses 1995, June 10 Karlsruhe, Germany 6. Tagung des Arbeitskreises KL im Berufsverband der Augenärzte Deutschlands e.V. Frequent-Replacement Lenses 1995, September 30 Clermont-Ferrand, France 25th ECLSO Congress Disposable and Frequent-Replacement Lenses in Germany 1996, January 20 Homburg/Saar, Germany 6th Contact Lens Course of the University Eye Clinic of Homburg/Saar (1) Disposable and Frequent-Replacement Contact Lenses; (2) Extended-Wear Lenses 1996, May 18 1996 Saarbrücken, Germany Seminar der Arbeitsgemeinschaft Südwestdeutscher Notärzte e.V. Emergencies in Ophthalmology 1997, January 25 Homburg/Saar, Germany 7th Contact Lens Course of the University Eye Clinic of Homburg/Saar Contact Lens Practice 1997, February 22 Neubrandenburg, Germany 4. Wissenschaftliches BVA-Kontaktlinsen-Kolloquium Neubrandenburg Fitting Frequent-Replacement Lenses 1997, May 24 Saarbrücken, Germany Seminar der Arbeitsgemeinschaft Südwestdeutscher Notärzte e.V. Emergencies in Ophthalmology

Lecture 3: Presentation of the Speaker

1998, March 7 Homburg/Saar, Germany 8th Contact Lens Course of the University Eye Clinic of Homburg/Saar Contact Lens Fitting Software 1998, May 23 Saarbrücken, Germany Seminar der Arbeitsgemeinschaft Südwestdeutscher Notärzte e.V. Emergencies in Ophthalmology 1998, June 24 Amsterdam, the Netherlands International Medical Contact Lens Symposium 1998 Management of Myopic Anisometropic Amblyopia with Contact Lenses in Children 1998, November 7 Saarbrücken, Germany Workshop besseres Sehen im Sport (Gesundheitsakademie Berlin) Contact Lenses and Water Sports 1998, November 19 Wiesbaden, Germany Wiesbadener Tagung des BVA Contact Lens Fitting Software 1999, February 27 Homburg/Saar, Germany 9. Homburger Einführungskurs in die Kontaktlinsenanpassung Therapeutic Principles of Anisometropic Amblyopia with Contact Lenses in Children 1999, May 15 Saarbrücken, Germany Seminar der Arbeitsgemeinschaft Südwestdeutscher Notärzte e.V. Emergencies in Ophthalmology 2000, April 28 Szeged, Hungary 4th Ametropia Kongresszus Management of Myopic Anisometropic Amblyopia with Contact Lenses in Children 2000, May 6 Saarbrücken, Germany Seminar der Arbeitsgemeinschaft Südwestdeutscher Notärzte e.V. Emergencies in Ophthalmology 2000, September 30 Antalya, Turkey 30th ECLSO Congress Can Extended Wear Be Safer than Daily Wear? 2000, November 4 Homburg/Saar, Germany 10th Contact Lens Course of the University Eye Clinic of Homburg/Saar Cosmetic and Color Lenses – An Overview 2000, November 18 Wiesbaden, Germany 1. Tagung der Augenärztlichen Kontaktlinsenexperten Anisomyopia and Contact Lenses in Children 2001, February 12 Las Vegas, USA CLAO Annual Meeting 2001 Sterile Infiltrates Related to Soft Contact Lens Wear 2001, March 9 Düsseldorf, Germany Augenärtzliche Akademie Deutschland, 2001 Infectious Risk and Extended Wear of Silicone Hydrogel Lenses 2001, March 28 Weiskirchen, Germany BVA-Fortbildung Complications Related to Extended Wear of Hydrogel Lenses 2001, May 11 Saarbrücken, Germany Seminar der Arbeitsgemeinschaft Südwestdeutscher Notärzte e.V. Emergencies in Ophthalmology

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2001, May 18 Nürnberg, Germany 14. Kongress der Deutschen Ophthalmochirurgen Extended Wear of Contact Lenses: Historical Review – Where Are We Going? 2001, June 6 Istanbul, Turkey 13th Congress of the European Society of Ophthalmologists Sterile Infiltrates Related to Soft Contact Lens Wear 2001, June 6 Istanbul, Turkey 13th Congress of the European Society of Ophthalmologists Extended Wear Complications with Conventional and Silicone Hydrogel Lenses 2001, June 21 Santander, Spain 31st ECLSO Congress First ECLSO Educational Program: Patient Evaluation Indications and Contraindications 2001, June 22 Santander, Spain 31st ECLSO Congress Incidence of CLPC in Contact Lens Wear 2001, October 1 Berlin, Germany 99th DOG Congress (German Society of Ophthalmology) Extended Wear – Past and Future 2001, November 3 Homburg/Saar, Germany 11. Homburger Einführungskurs in die Kontaktlinsenanpassung Contact Lenses and Sports 2002, February 2 Leipzig, Germany 1. Kontaktlinsentag Mitteldeutschland Leipzig Contact Lenses and Sports 2002, February 17 Münster, Germany 13. Ophthalmologisch-Optische Fortbildung Contact Lenses: Where Do We Go? 2002, April 24 Sydney, Australia 29th International Congress of Ophthalmology Exciting Advances in the Field of Contact Lenses 2002, September 26 Bordeaux, France 32nd ECLSO Congress 2nd ECLSO Educational Program: Patient Evaluation Indications and Contraindications 2002, September 27 Bordeaux, France 32nd ECLSO Congress Cornea Infiltrates in Contact Lens Wearers 2002, September 28 Bordeaux, France 32nd ECLSO Congress Therapeutic Use of Silicone Hydrogel Lenses

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Membership of Medical and Scientific Organisations: Berufsverband der Augenärzte Deutschlands e.V. (Germany) Société Française d’Ophtalmologie (France) European Contact Lens Society of Ophthalmologists Medical Contact Lens and Ocular Surface Association (UK) Société Française des Ophtalmologistes Adaptateurs de Lentilles de Contact (France)

Mély

Lecture 3 Ophthalmologica 2004;218(suppl 1):33–38 DOI: 10.1159/000079465

Therapeutic and Cosmetic Indications of Lotrafilcon A Silicone Hydrogel Extended-Wear Lenses René Mély Saarlouis, Germany

Introduction

‘Extended wear’ is defined as the use of contact lenses for extended periods of time (up to 6 nights and 7 days) without removal and care whereas ‘continuous wear’ is contact lens wear for longer periods of up to 29 nights and 30 days. The oxygen supply to the cornea and the risk of infection are the major challenges when contact lenses are worn on an extended- or continuous-wear basis. To understand the problems related to oxygen supply and contact lens wear, it is important to first review some aspects of the physiology of the cornea when no lenses are worn. Under opened-eye conditions, the cornea relies mainly on the atmosphere to supply oxygen (21% or 155 mm Hg). Under closed-eye conditions, oxygen is supplied by blood vessels of the limbus and the palpebral conjunctiva as well as the aqueous humor. The partial pressure of oxygen drops to 55 mm Hg, and this relative hypoxia leads to a so-called physiological corneal edema which results in a swelling of 4% of the stroma. When contact lenses are worn on the eye, there are two possible routes of oxygen supply. The first one is pumping oxygenated tears under the lens, which depends on 3 factors: E The condition of the eyelids (closed or not). Tear exchange under the lens is much higher under openedeye conditions, but some pumping effect remains even under closed-eye conditions due to the rapid eye movements occurring during sleep.

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E The lens stiffness or modulus which is very high for rigid gas-permeable (RGP) lenses, low for conventional soft contact lenses, intermediate for silicone hydrogel lenses. The stiffer the lens material, the better the tear pumping effect. E The lens fit: tear exchange is better when the lens fit is flat as opposed to a tight fit. The second route for oxygen supply is the passage of oxygen through the lens. The oxygen permeability (Dk) is a property of the lens material. The thickness of the lens (L) is related to the design of the lens (brand) and to material properties but also to the power of the lens. The oxygen transfer through a contact lens is therefore best described by the oxygen transmissibility or Dk/L which is an in vitro measurement of the passage of oxygen through a sample of material of specified thickness. The oxygen transmissibility of a lens being usually given for a –3.0 dpt lens, it is of major importance to consider this point especially in case of aphakia in children, where the power of the contact lens may exceed 30 dpt. The contact lens being a barrier to the direct diffusion of oxygen from the atmosphere to the cornea, it is clear that the size has an impact on the oxygen supply. As RGP lenses have only half the surface of a soft contact lens and are not covering the entire cornea they may provide a better oxygen supply at equal Dk/L.

René G. Mély Zeughausstr. 76 DE–66740 Saarlouis (Germany) Tel. +49 6831 501 5850, Fax +49 6831 501 5851, E-Mail [email protected]

Minimum Dk/L Values to Avoid Corneal Anoxia

The relationship between oxygen transmissibility and corneal edema has been examined by Holden and Mertz [1] in 1984. It was found that under daily-wear conditions contact lenses must have at least a Dk/L of 24 ! 10 –9 to avoid anoxia. With eyes closed, the critical Dk/L level to limit cornea edema to the physiological level of 4% observed without lenses was found to be 87 ! 10 –9. In a more recent study published in 1999, Harvitt and Bonanno [2] updated Fatt’s mathematical model of the distribution of oxygen tension across the cornea and included findings that corneal oxygen consumption increases with acidification This study found much higher minimum levels of oxygen transmissibility. Under opened-eye conditions, the minimum Dk/L required to avoid anoxia of the basal epithelial cells was found to be 23 ! 10 –9 and 35 ! 10 –9 for the entire corneal thickness. Under closed-eye conditions, the minimum Dk/L required to avoid anoxia of the basal epithelial cells was found to be 89 ! 10 –9 whereas the minimum Dk/L required to avoid anoxia of the entire corneal thickness was found to be 125 ! 10 –9. Such high levels of oxygen transmissibility can only be reached by very few hyper-O2-transmissible lenses. The Dk of conventional hydrogels is mainly related to the water content of the lens. As high-water-content lenses are thicker than low-water-content lenses, the overall oxygen transmissibility cannot, even in the best cases, surpass a level of approximately 40 ! 10 –9 which is far below the minimal requirements of Holden and Mertz [1]. Silicone having the highest oxygen permeability of all contact lens materials (400 ! 10 –11), it is not surprising that the Dk/L of silicone elastomer lenses is much higher. Two lenses are available (Silflex®, Wöhlk, Germany, and Silsoft®, Bausch & Lomb, USA); they are mainly used to correct aphakia in children on an extended-wear basis and have a Dk/L of 133 ! 10 –9 for a 0.30-mm-thick aphakic lens. RGP lenses can also reach very high Dk/L levels as most of these new materials include silicone copolymers but only one material (Tisilfocon A, Menicon Z®; Dk/L 125 ! 10 –9) fulfils the requirements of Harvitt and Bonanno [2] for a safe extended wear. The new silicone hydrogel material reaches the highest levels of oxygen transmissibility of all presently available lenses. This is related to a unique combination of silicone with high oxygen permeability and hydrogel with good fluid transport. Two lenses are now available: the Pure Vision® lens (balafilcon A, Bausch & Lomb) which has a

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Ophthalmologica 2004;218(suppl 1):33–38

Dk/L of 110 ! 10 –9 and the Focus Night & Day® lens (lotrafilcon A, CIBA Vision), the only lens with a Dk/L (175 ! 10 –9) far over the minimum requirements of Harvitt and Bonanno [2] for a safe extended wear (125 ! 10 –9).

Historical Background

The first modern use of a contact lens as bandage lens and drug delivery after cataract surgery has been reported in 1886 by Galezowski [3], a French ophthalmologist. He successfully used gelatine shields soaked in cocaine and sublimate as an anesthetic and antiseptic bandage after cataract surgery. Some of the scleral lenses used from the end of the 19th century have also been used for therapeutic purposes in irregular corneas, but these lenses could only be worn for a few hours and never overnight. The real breakthrough came with Otto Wichterle (1913–1998) who was a professor of macromolecular chemistry at the Czech Technical University in Prague. In 1960, he used a phonograph motor and a child’s building kit to develop a spin-casting technique for shaping hydroxyethyl methacrylate into the first soft contact lenses [4]. About 10 years later, the first reports about the therapeutic use of these new hydrophilic lenses were published by Gasset and Kaufmann [5] in the American Journal of Ophthalmology. Following these reports, the therapeutic use of extended-wear soft lenses has been first approved by the FDA in 1979, and the extended wear of soft lenses for cosmetic purposes has been approved in 1981. The extended wear of silicone elastomer lenses and of RGP lenses has been approved a few years later in 1986. The approval for extended wear of soft lenses for cosmetic purposes in 1981 resulted in a great popularity of this very convenient wear modality especially in the USA and in Scandinavia. In 1988, approximately one third of the US soft lens wearers and half of the Danish wearers had adopted this wear modality. In other western countries like Germany, patients and contact lens fitters were more cautious and the extended wear of soft contact lenses represented only 2–3.5% of the wearers. Unfortunately, the enthusiasm of American and Scandinavian lens wearers was soon to be shadowed by reports in the medical literature and the media about a dramatic increase in severe contact-lens-induced complications. In an important study published by Poggio et al. in 1989 [6], it became obvious that the risk of keratitis was much higher with extended-wear lenses (20.9 cases per 10,000 wearers) as compared with daily-wear lenses (4.1/10,000). In

Mély

Table 1. Estimated annualized incidence

of ulcerative keratitis per 10,000 wearers in 3 major studies Poggio et al. [6], 1989 Nilsson and Montan [8], 1994 Cheng et al. [9], 1999

Daily-wear conventional soft CL

Daily-wear frequent replacement

Extended-wear Extended-wear conventional frequent soft CL replacement

4.1 0.51 3.5

– 0.16

20.9 3.12 20

– 4.17

Only hospitalized cases have been considered in the study of Nilsson and Montan, whereas Poggio et al. and Cheng et al. conducted a survey of all ophthalmologists in the study area.

another study published the same year by Schein et al. [7], the risk of keratitis was found to be 5- to 15-fold higher with extended-wear lenses as with daily-wear lenses. One attempt to diminish the risk of contact-lensinduced keratitis was to improve lens hygiene by introducing disposable lenses at the end of the eighties. An interesting study published by Nilsson and Montan [8] in Sweden in 1994 focused on that point. The results showed that the risk of keratitis could be reduced with daily disposable lenses but paradoxically not for extended-wear disposable lenses. The overall risk of this study is much lower due to the fact that only hospitalized and therefore severer cases had been taken into consideration by Nilsson and Montan [8], whereas Poggio et al. [6] used reports of all ophthalmologists in the study area, a certain number of cases being possibly less severe cases of infiltrates misdiagnosed as infectious keratitis. Interestingly a more recent study performed in 1999 in the Netherlands by Cheng et al. [9] using a similar design as Poggio et al. [6] found also very similar results as these authors (table 1). There are fewer studies about the risk of keratitis with bandage lenses. As in most cases of therapeutic use the integrity of the cornea is compromised, it is not surprising that the incidence is much higher in such eyes. In an overview published by Liesegang in 1997 [10], the risk of keratitis among therapeutic-lens wearers was estimated to be approximately 50 cases/10,000 wearers/year. Strict hygiene and antibiotic prophylaxis in case of an epithelial defect are therefore recommended.

Table 2. Frequency (%) of bacteria colonizing lenses during extended wear of low-Dk versus lotrafilcon A lenses [11]

Bacteria

Low-Dk/L High-Dk/L lenses lenses (lotrafilcon A)

Sterile lens samples Coagulase-negative staphylococci Propionibacterium spp. Gram-negative bacteria Staphylococcus aureus

28 47 48 3 0

27 54 43 2 2

A variety of biochemical, cellular and microbial changes occur in the closed eye that predispose to both inflammatory and infectious adverse responses.

When contact lenses are worn on an extended-wear basis, they usually get contaminated by nonpathogenic bacteria of the ocular environment. In a comparative study by Keay et al. [11], only one third of the lenses remained sterile; however, contamination with gram-negative rods was quite rare (table 2). This endogenous bacterial contamination of extended-wear lenses plays an important role in inflammatory events such as contact-lensinduced acute red eye, contact-lens-induced peripheral ulcers (fig. 1) or other cornea infiltrates, but it is not the source of severe infectious keratitis. It is well known that hypoxia of the cornea causes metabolic complications such as endothelium changes. It is also likely that hypoxia delays wound healing. The integrity of epithelium cell junctions may also be compromised by edema causing microerosions which allow bacteria to penetrate into the cornea. Nevertheless, the key role of hypoxia in the pathophysiology of cornea infections has only been proved in recent years by several studies demonstrating that the major risk factor is the increase in bacterial binding to the cornea induced by hypoxia. These studies performed by Ren et al. [12, 13] and Cavanagh et al. [14] have shown that there is a significant

The 16th CIBA Vision Symposium

Ophthalmologica 2004;218(suppl 1):33–38

Pathophysiology of Infectious Keratitis

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Fig. 1. Contact-lens-induced peripheral ulcers related to extended wear of soft contact lenses. These innocuous infiltrates resolve in most cases without treatment.

Fig. 2. Keratopathia bullosa after multiple surgery for retinal detachment. Excellent pain relief with a lotrafilcon A bandage lens. No complications after 3 years of follow-up.

correlation between binding of Pseudomonas aeruginosa to the epithelium and the Dk/L of the lenses. Bacterial binding was reduced as oxygen transmissibility increased. Hypoxia being a major risk factor for microbial keratitis, one would expect silicone hydrogel lenses to be much safer than the previous low-Dk hydrogel lenses. The first lenses have been launched in 1999, and they have been approved by the FDA for continuous wear in 2001. Based on lens sales data, there are approximately 850,000 wearers worldwide. According to data published on the internet (www.siliconehydrogels.org) by the research group of Brien Holden and Deborah Sweeney (CCLRU/CRCERT, Sydney, Australia), only 51 cases of microbial keratitis have been reported worldwide up to now. This number is probably largely underestimated. It is more realistic to consider the situation in just one country like Australia where probably all cases have been reported to the CCLRU. The number of silicone hydrogel wearers in this country is approximately 70,000; up to now there are 10 reported cases of microbial keratitis related to the extended wear of these lenses, giving an estimated rate of 1 keratitis per 7,000 patients. This is much less than the rate of 1/500 found by Poggio et al. [6] or Cheng et al. [9] with low-Dk extended-wear lenses and even less than the rate found by the same authors with daily-wear lenses (1/ 2,500). In his summary of the world symposium on extended wear in 2002, Cavanagh [15] estimates that the

risk for infection with these new materials shows at least a 10-fold decrease. The incidence of microbial keratitis related to therapeutic use of silicone hydrogel lenses is not precisely known as only two small studies have been published. The first study published by Lim et al. in 2001 [16] used the Pure Vision contact lenses on 54 eyes mostly after surgery (laser in situ keratomileusis, photorefractive keratectomy, perforating keratoplasty ...). The lens was judged successful in 96% of cases (wound healing, pain relief); no major complications were observed (1 infiltrate). Another retrospective study using the Focus Night & Day lens on 41 eyes has been published recently [17]. The overall treatment success was judged as fully successful in 78% of all cases with excellent results for pain relief in 86% of cases. One infiltrate was observed in that study as well as 1 case of suspected keratitis which resolved quickly under antibiotics and healed without visual loss.

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Ophthalmologica 2004;218(suppl 1):33–38

Indications for Silicone Hydrogel Lenses

High-Dk silicone hydrogel lenses are the only soft lenses fulfilling the minimum requirement for extended wear established by Harvitt and Bonanno [2]; it is therefore obvious that they are the first choice whenever therapeutic lenses are indicated.

Mély

Fig. 3. Trophic ulcer after cataract surgery and keratoplasty.

peutic lenses, it is important to make sure that there is no underlying infection of the damaged surface of the cornea. It seems always prudent to prescribe a prophylactic antibiotic therapy whenever the epithelium is compromised. In the 2 cornea infiltrates observed in my own practice [17], no antibiotic prophylaxis had been given. Furthermore, in order to avoid also iatrogenic infection from contaminated bottles, anesthetic and diagnostic eye drops should, when necessary, be used as single-dose units. After bandage lens fitting, patients should always be reviewed the next day and eventually the following days depending on the evolution and the condition of the epithelium. Apart from their use as therapeutic lenses, silicone hydrogels may also be prescribed whenever there is a medical indication for continuous-wear lenses, as far as the refraction of the patient and lens fit are appropriate. This may be the case for many pediatric indications such as unilateral high myopia, aniseikonia, anisometropia or penalisation. Silicone hydrogel lenses can also be very successfully used as piggyback lenses, and they have led to a revival of this technique. Among the various medical indications for silicone hydrogel continuous-wear lenses, the use as drug delivery is the only one which seems not to be successful. As suggested by a recent study of Schiffer in Germany, silicone hydrogel lenses are not indicated as drug reservoir, since drugs such as ketotifen and cromoglycate are absorbed and therefore released in insignificant amounts. Last but not least, two thirds of the patients are interested by the continuous-wear modality for cosmetic purposes, but for historic reasons most of contact lens fitters are still opposed to it. This attitude seems not justified with the new hypertransmissible materials since the risk of major complications seems not to be greater than with low-Dk hydrogel daily-wear lenses. It is also well known that many patients wear their lenses overnight without consulting their eye care professional while other contact lens wearers such as nurses or physicians may wish for continuous-wear lenses when working at night. For all these reasons, silicone hydrogel lenses are the best option, in many cases offering a comfortable and safe alternative to refractive surgery.

Therapeutic contact lenses are used for the following purposes: E pain relief in cases such as keratopathia bullosa (fig. 2), cornea injuries, recurrent erosions, corneal dystrophy, keratopathia filiformis E improvement of wound healing after cornea injuries, trophic ulcers (fig. 3), after refractive surgery E protection of the cornea in cases such as trichiasis, neuroparalytic keratitis E drug delivery The advantages of bandage contact lenses versus patching are a better pain relief and therefore a shorter disablement. Binocular functions are preserved so that car driving is in most cases possible. The oxygen supply to the cornea is under opened-eye conditions much better with a silicone hydrogel bandage lens than with a normal patch, and this should also, in addition to the mechanical protection of the eye, improve wound healing. Silicone hydrogel bandage contact lenses are now in most cases the treatment of choice in my own practice. The development of silicone hydrogel lenses has led the Berufsverband der Augenärzte and Deutsche Ophthalmologische Gesellschaft, the two major German societies of ophthalmology, to publish guidelines concerning the use of therapeutic lenses. Since silicone hydrogel lenses are the only lenses providing a sufficient oxygen supply to the cornea, these guidelines state that lenses with a Dk/L under 125 ! 10 –9 should not be used as therapeutic lenses, unless there is a medical reason to do so. Among other recommendations before prescribing thera-

In conclusion, the continuous wear of silicone hydrogel lenses is a safe option for therapeutic as well as cosmetic purposes. Patient selection regarding medical history and compliance is the first step before prescribing silicone

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lenses. Patient information, especially concerning lens hygiene and risk factors, is the second point in the prevention of severe complications. Swimming with lenses is a major risk of keratitis [18] and is not recommended when wearing continuous-wear lenses. Patients should also be advised not to wear their lenses when they are sick. More precise answers on the rates of microbial keratitis should be available in 2004. Future improvement of lens

material, design and surface biocompatibility should improve wear comfort and reduce mechanical problems which are sometimes related to the stiffness of the lenses. Although the safety of silicone hydrogel lenses is much higher as compared to low-Dk lenses, research will have to lower the rates of microbial keratitis and inflammatory adverse events further, maybe by the incorporation of antimicrobial surface agents, making continuous wear the wear modality of the future.

References 1 Holden B, Mertz G: Critical oxygen levels to avoid cornea edema for daily and extended wear contact lenses. Invest Ophthalmol Vis Sci 1984;25:1161–1167. 2 Harvitt D, Bonanno J: Re-evaluation of the oxygen diffusion model for predicting minimum contact lens Dk/L values needed to avoid corneal anoxia. Optom Vis Sci 1999;76:712– 719. 3 Galezowski X: Sur la plaie cornéenne dans l’extraction de la cataracte et sur les moyens de prévenir la suppuration. Bull Mém Soc Fr Ophtalmol 1886;4:217–226. 4 Wichterle O, Lim D, Dreifus M: K problému´ kontaktnich cˇocˇek (On the problem of contact lenses). Cesk Oftalmol 1961;17:70–75. 5 Gasset A, Kaufmann H: Therapeutic uses of hydrophilic contact lenses. Am J Ophthalmol 1970;69:252–259. 6 Poggio EC, Glynn RJ, Schein OD, et al: The incidence of ulcerative keratitis among users of daily-wear and extended-wear soft contact lenses. N Engl J Med 1989;321:779–783.

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7 Schein OD, Glynn RJ, Poggio EC, et al: The relative risk of ulcerative keratitis among users of daily-wear and extended-wear soft contact lenses. A case-control study. N Engl J Med 1989;321:773–778. 8 Nilsson SE, Montan PG: The hospitalized cases of contact lens induced keratitis in Sweden and their relation to lens type and wear schedule: Results of a three-year retrospective study. CLAO J 1994;20:97–101. 9 Cheng KH, Leung SL, Hoekman HW, Beekhuis WH, Mulder PG, Geerards AJ, Kijlstra A: Incidence of contact-lens-associated microbial keratitis and its related morbidity. Lancet 1999;354:181–185. 10 Liesegang TJ: Contact lens related microbial keratitis. I. Epidemiology. Cornea 1997;16: 125–131. 11 Keay L, Willcox MDP, Sweeney DF, et al: Bacterial populations on 30-night extended wear silicone hydrogel lenses. CLAO J 2001;27:30– 34. 12 Ren DH, Petroll WM, Jester JV, et al: The relationship between contact lens oxygen permeability and binding of Pseudomonas aeruginosa to human corneal epithelium cells. CLAO J 1999;25:80–100.

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13 Ren DH, Yamamoto K, Ladage PM, et al: Adaptative effects of 30-night wear of hyper-O2 transmissible contact lenses on bacterial binding and corneal epithelium: A 1-year clinical trial. Ophthalmology 2002;109:27–30. 14 Cavanagh HD, Ladage PM, Li L, et al: Effects of daily and overnight wear of a novel hyper-O2 transmissible soft contact lens on bacterial binding and corneal epithelium: A 13-month clinical trial. Ophthalmology 2002;109:1957– 1969. 15 Cavanagh HD: How popular will continuous wear become? Discussion and summary. CLAO J 2003;29:S166. 16 Lim L, Tan DT, Chan WK: Therapeutic use of Bausch & Lomb PureVision contact lenses. CLAO J 2001;27:179–185. 17 Montero JM, Sparholt J, Mély R, Long B: Retrospective case series of therapeutic applications of lotrafilcon A silicone hydrogel soft contact lenses. Eye Contact Lens 2003;29:72–75. 18 Holden BA, Sweeney DF, Sankaridurg PR, et al: Microbial keratitis and vision loss with contact lenses. CLAO J 2003;29:S131–134.

Mély

Question and Answer Ophthalmologica 2004;218(suppl 1):39–41 DOI: 10.1159/000079466

Question and Answer Sessions with Dr. Paulus T.V.M. de Jong

Tokyo

Chairman: Dr. Yoshihisa Oguchi (Department of Ophthalmology, School of Medicine, Keio University) Dr. Oguchi: Thank you very much, Dr. de Jong. It was a very interesting and instructive lecture. Dr. de Jong discussed the Rotterdam Study on AMD (age-related macular disease). I am surprised that the No. 1 factor in blindness among Caucasians is AMD, and that diseases differ from race to race. Now I would like to invite questions and comments from the audience. Dr. Osamu Katsumi (Tokyo): Thank you, Professor de Jong. I have two questions. One regards the incidence. Does it differ according to locations, i.e. does it matter whether you live in Rotterdam or in Florida? Are there any differences in qualities of sunlight? Also, I was very surprised to see the results of hyperopia as a risk factor. What if myopia is more like 6 dpt? Dr. de Jong: Your first question was if the incidence in Caucasians differs. We compared our data with those from the Beaver Dam Study in the USA and with the Blue Mountain Study in Australia. Incidences were slightly lower in the Rotterdam Study, but it was not a big difference. We also had a slightly lower prevalence in Rotterdam. This might be either due to small differences in examination techniques or to environmental factors. At this moment we are analyzing the data from the EUREYE Study. This study examines about 4,000 respondents from 8 different countries in Europe from Norway to Greece. Generally speaking, AMD prevalence data seem

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the same all over Europe. I cannot give definite figures yet, but we think that there is not really a big difference there despite differences in light exposure. As to your questions about myopia ... Myopia is of course a problem while defining AMD for two reasons. If we have a neovascular disciform reaction in the macular area of a –8 or –10 dpt myopic eye, we are not sure if that is due to myopic Fuchs degeneration or due to AMD. In general, we say we need to see drusen before we call it AMD. AMD is a diagnosis by exclusion. So when you have an aspecific scar in the macular area without clear drusen, we can neither rule out AMD nor for example juvenile macular degeneration or presumed ocular histoplasmosis. Myopic fundi, at least in Caucasians, are less pigmented than hyperopic eyes, especially when you have a large field of choroidal atrophy and white myopic degenerations. You cannot see the drusen very well anymore. This may make it more difficult to detect drusen. Each diopter shift towards hyperopia gave a 6% higher rate of AMD. So, we think it is not due to confounding factors or to missing a few correct diagnoses. Asians have more myopia than Caucasians with its known complications, but a good thing seems to be that this leads to less AMD. Dr. Oguchi: Dr. Katsumi asked two questions. The first question was if there is any relationship between AMD incidence and location. Dr. de Jong related that he took part in prevalence studies in 8 locations in Europe, but there was no obvious difference in prevalence among locations. The second was about hypermetropia. Honestly speaking, it is a first time for me to hear that a higher level of hypermetropia causes more AMD. As there are more

farsighted people in Europe than in Japan, there may be more AMD cases in Europe than in Japan. More questions from the audience? Dr. Yutaka Imamura (Keio University): Thank you very much for your wonderful lecture. In Japan, more males, 3 times more males than females, are likely to show AMD development while the data from Dr. de Jong show more females with prevalent AMD. Would you explain this, please? I guess that more Japanese males than females smoke. Dr. de Jong: My first remark regards how you found out that Japanese males have more AMD than females. Are these clinic-based data or population-based data? If you are talking about clinic-based data, they can be confounding because, for example, perhaps the male goes to the doctor earlier than the female or the other way around. I am not sure if it is common in Japan, but I know that in parts of China or in India the male is considered more important than the female, so they send boys to the doctor earlier than girls. So this may lead to bias. Before we accept that males have triple the AMD rate, I would like to know exactly where you got the data from. I must say, however, that in the pooled data from the Beaver Dam, Blue Mountains and Rotterdam Studies there was no longer any difference in AMD prevalence between males and females. Dr. Imamura: Thank you. How about smokers in Holland? Are males more likely to smoke than females? Dr. de Jong: It seems there are more smokers in Japan than in Holland. So is there here a gene protecting against smoking effects? Holland has another problem. Older males smoke less. Females smoke more and more. So, we see a rising incidence of lung cancer in women. Our main concern is that the highschool population smokes a lot. It is so difficult to teach these youngsters not to smoke. I have no exact data why people start smoking, but I know the bad side effects for the women. I also have read that the type of lung cancer in women is even worse than in men because it starts more often multilocally and in the lung periphery than in the major bronchi. Dr. Yoshiko Matsuhashi (Nagoya City): I would like to ask you one more question. Which causes the higher percentage of AMD, hyperopia, myopia or presbyopia? Dr. de Jong: Hyperopia is a much higher risk factor than myopia. In all our age strata, myopia was protective against AMD. I am not aware of any report on the association between presbyopia and AMD after correcting for age. Dr. Oguchi: Thank you very much, Dr. de Jong.

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Osaka

Chairman: Prof. Akira Negi (Department of Ophthalmology, Kobe University) Dr. Negi: Thank you Dr. de Jong for your splendid lecture. Let me invite questions from the audience. Dr. Yasuaki Kuwayama (Osaka Kouseinenkin Hospital): I have two questions. First, I would like to ask whether drusen in AMD are pathological or they simply represent an ageing phenomenon. While your lecture suggested that drusen are early indications of AMD, some believe that drusen are an ageing phenomenon. Do you think drusen by themselves constitute the pathology of earlystage AMD? Next, you mentioned the study in the USA, in which nutritional supplements prevented patients from developing AMD. Do you think patients with drusen should be instructed to follow well-balanced nutrition? Does such an intervention reduce the risk of disease onset? Dr. de Jong: In my view, drusen are a mixture of ageing phenomenon and pathology when we see the clear rise in prevalence with ageing. I also consider drusen one manifestation of malfunctioning retinal pigment epithelium (RPE). If it were pure ageing I had expected more people over the age of 75–80 years to have many or larger drusen. We have different hypotheses why drusen lead to AMD, for example antioxidant deficiency, inflammation, or vascular growth factor upregulation. Some groups have been giving more attention to the type of drusen. Professor Chakravarthy from Belfast (Queen’s University and Royal Group of Hospitals) looked at about 200 patients with stage 4 AMD. She had a picture from many years earlier of these cases. People with many drusen developed more occult neovascular AMD, people with few drusen more classic neovascular AMD. So we now think that drusen are a manifestation of a dysfunctioning RPE. And the more drusen you have, the more sick your RPE is. We looked at many types and different clinical assessments of drusen and could not find correlations with the type of late AMD. However, the larger the area covered by drusen in the macula, the higher the chance of late AMD, but we still consider drusen to be a hallmark of AMD at all ages. Dr. Kuwayama: I understood, but as you know, some doctors think that drusen are only an ageing phenomenon and not something particular to the disease. Do you think drusen represent very-early-stage AMD? Dr. de Jong: Most people about the age of 70–75 have a few tiny drusen (on histology 10–20 years earlier), but we also found people who had no drusen on ophthalmoscopy.

Question and Answer Sessions with Dr. Paulus T.V.M. de Jong

So I don’t think drusen are necessarily present in every person, and I consider drusen, especially 1125 Ìm, to represent early AMD and to be a risk factor for late AMD. AMD is multifactorial, a combination of genetics and environment. We calculated that about 27% of AMD is due to a genetic contribution and the remainder is due to the environment, e.g. food, drinking, smoking and other factors. Dr. Kuwayama: So the answer to the first question is ‘yes’, right? My second question is that if we find drusen in a patient, should we always recommend good nutrition? Dr. de Jong: With regard to the AREDS Study with nutritional supplements I am convinced after seeing our data on antioxidant intake in the diet that a well-balanced diet with vitamin C and E, ß-carotene and zinc protects against AMD. I think that would be a good suggestion. People having a diet with above median antioxidant intake in the Rotterdam Study had less AMD. So if I have a patient with stage 2 AMD or higher, I recommend taking antioxidants, but not in such high doses as in the AREDS Study, 5 times more than the recommended daily dose. I would like everyone with large drusen to change dietary habits and eat more green vegetables. Also zinc seems especially important. I’m not sure if rice contains much zinc, but fish, poultry, meat, dairy products and brown bread do. So I would recommend taking them. Dr. Yozo Miyake (Nagoya University): Let me ask an additional question. I noticed the report of a very largescale supplementation study in the archives dating back a few years ago. The study examined categories 1–4. While the data showed no effect of supplementation in categories 1 and 2, some benefits were observed in relatively advanced categories 3 and 4. I’m much interested in knowing whether or not the current evaluation system as mentioned by Dr. Kuwayama is valid for the evaluation of early-stage AMD. As Dr. de Jong pointed out in the lecture, the use of autofluorescence and other methods may facilitate a more accurate assessment of early-stage severity of disease. When we look at the risk factors for AMD, we find there are several vascular factors, such as hypertension and arteriosclerosis. May I ask your opinion as to whether diabetics have more AMD? Dr. de Jong: I’m sorry, I’m not sure if I caught all your questions. The AREDS Study showed antioxidant protection for the late stages. We now also for the early stages. My answer to the last question whether people with diabetes mellitus have more AMD is that we did not find this association in the Rotterdam Study. One explanation

might be survival bias because people with severe diabetes have a shorter life expectancy and thus die before they can develop AMD. We looked on the other hand at the life expectancies of AMD, glaucoma and cataract, and when we adjusted for all confounders, we found no higher mortality in people with these diseases. So my feeling is that diabetes is not a major risk factor for AMD. Does that answer your question? Dr. Negi: Recent studies showed that the incidence of polypoidal choroidal vasculopathy (PCV) is very high in Japan. I wonder how the situation in Japan can be compared with that in western countries. In Japan, polypoidal vasculopathy accounts for 30–40% of neovascular lesions. Dr. de Jong: We can only correctly diagnose polypoidal disease when you have angiograms and preferably indocyanine green ones. In the Rotterdam Study, we made no angiograms, and thus it is hard to identify PCV. We can only guess from color fundus photographs for evidence of PCV. As far as I hear from incidental clinic-based reports, PCV is much more common in Japan than in Europe. I would very much like to see fundus pictures made in Japanese epidemiological AMD studies to compare them with ours. Dr. Negi: The population in the Rotterdam Study included a substantial number of black people. I think the prevalence among black people may be somewhat lower than the prevalence in our data. I think their lifestyle is similar to the western style. Do the initial diagnostic findings of AMD in black people resemble those seen in Caucasians, or do they present more with AMD associated with PCV? Dr. de Jong: I am not quite sure if African Americans have more PCV than whites. I think that African Americans have the same prevalence of early AMD, but they have less late-stage AMD (stage 4). I do not know of any studies comparing dietary intake or other lifestyle factors. I know for example that in a study, African blacks and Aborigines in Australia had less AMD. But I cannot compare the lifestyles or even the evidence for the higher frequency of polypoidal disease in blacks than in Caucasians. By the way, in the Rotterdam Study 99% were of Caucasian origin. Dr. Negi: Thank you very much. Regarding epidemiological studies, Japanese researchers have recently concluded a study on glaucoma and obtained very accurate data for the first time in Japan. The results were considerably different from those of western studies. As we understand from this experience, epidemiological studies are important as the bases for a scientific approach. Thank you very much again, Dr. de Jong.

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Question and Answer Ophthalmologica 2004;218(suppl 1):42–44 DOI: 10.1159/000079467

Question and Answer Sessions with Dr. Hidetoshi Yamashita

Tokyo

Chairman: Dr. Koji Kurata (Chairman of the Tokyo Association of Ophthalmologists) Dr. Takaaki Hirado (Kanto Rosai Hospital): As you pointed out, the recent increase in diabetics in the Japanese population is related to the aging of society and increased calorie intake. If we look at people in the same age range, with the same amount of physical exercise and with the same calorie intake, would you say those with higher fat intake are more prone to diabetes? Dr. Yamashita: In a statistical sense, it is a correct statement. In particular, animal fat is considered detrimental. Vegetable oil and fish oil are believed to be beneficial. Actually, the low-fat diet recommended in the Diabetes Prevention Program is similar to the average diet of Japanese people today. However, there are data suggesting that Japanese people need to restrict their fat intake even more than Caucasians, because Japanese people are more likely to be overweight than Caucasians. Your statement is right. Fat intake is a major factor. Dr. Kimimichi Okuyama (Sangubashi Eye Clinic): In the case of NIDDM, strict control sometimes causes the problem of bleeding. How strict do you think the control should be? Does sudden control result in bleeding? Do you have any new data concerning blood sugar control? Dr. Yamashita: On this theme, there were pioneer studies by Professor Hirata at Tokyo Women’s Medical College and Professor Fukuda who was then at Ryukyu University, and their work has been confirmed in Europe. According to their results, excessive control is not advisable. Epidemiological data from the Kumamoto study showed that no more than 3% in 6 months is recommended. Internal

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medicine physicians say that we cannot set a target as we like and hit the target. But sudden control is by no means recommended. There are 2 important points. First, because no control means further aggravation, we must always try to reduce blood glucose levels. Second, although patients with good control may show some aggravation, they very rarely experience dramatic aggravation. We conducted a study in cooperation with the group of Professor Sekihara, from the 3rd Department of Internal Medicine, Yokohama City University. When we compared patients who showed a decrease and then an increase and patients who showed a decrease and remained low, the former developed retinopathy more frequently. If a patient shows a decrease and some aggravation is observed, we should hang in there. Do phototherapy and other necessary procedures, and patiently try to keep levels low. Then, the condition will not progress, and the risk will be relatively low. Do not allow high levels to persist. We must always bring high levels down, but it should be done slowly and the levels kept low. I think this is the best strategy. Dr. Kurata: Then, it’s time to end this session. Thank you very much, Dr. Yamashita.

Osaka

Chairman: Dr. Yozo Miyake (Department of Ophthalmology, Nagoya University) Dr. Miyake: Thank you, Dr. Yamashita. Your lecture covered the wide range of topics you study, starting from the present state of diabetes in Japan and including the discussion of future therapies. Are there any questions or comments?

Dr. Toshiaki Aritake (Seto City): Thank you for your fine lecture. I am practicing in a small clinic. I attended this seminar expecting to get some practical knowledge of drugs. I sometimes use ACE inhibitors such as tanatril and angiotensin blockers for type 2 diabetic retinopathy. Basically, we use them in cases with mild hypertension and nephropathy. I also use aspirin at times, in particular for end-stage retinopathy. My first question is: do you have experience in these types of treatment? Next, we have recently heard much about thalidomide in newspapers and other media. It is used for multiple myeloma and leukemia, and the purpose is the suppression of vascular contraction. Are you aware of any reports on the use of thalidomide for retinopathy? Dr. Yamashita: With respect to aspirin, we have done a study called ETDRS. As far as the evidence from this study showed, it is not effective in retinopathy. Aspirin has been shown to have substantial benefit in cardiovascular conditions. Oral use of 100 mg/day provides a prophylactic effect against cardiovascular diseases. So, according to available evidence, oral aspirin may be effective mainly on macroangiopathy. We need further studies to see whether or not it is really ineffective in retinopathy. It is possible that it may be effective in properly selected target populations. There are some reports on the benefit of aspirin in early stages of retinopathy. Such observations have not been confirmed by evidence from largescale studies. At least, oral aspirin does not aggravate retinopathy. It is considered a good treatment choice targeted at macroangiopathy. With respect to thalidomide, I am not sure but I think a trial in the field of ophthalmology may be ongoing, expecting effectiveness in the inhibition of neovascularization. Although no such study is conducted in Japan, I have heard about a number of experimental studies. I speculate that a clinical trial may have been initiated. I am sorry I have not been following the developments in this direction. Like aspirin, actual confirmation of efficacy awaits future large-scale epidemiological studies. Dr. Miyake: Probably 10 years in the future, medication will be the mainstay of treatment for diabetes. There will be various developments. Theoretically we already have very good drugs, such as aldose reductase inhibitors, but the reality is not as rosy. What do you think is causing this situation? Dr. Yamashita: My speculation is that the problem is a complete lack of efficacy evaluation in various forms of disease. There must be a drug that is effective in a given form of disease. The condition of retinopathy in individu-

al patients must be understood on a molecular level, but we lack this knowledge. We have only very crude measures for evaluating which drug should be used in which patient. So, in large-scale epidemiological studies, any differences are likely to disappear. Patients having similar blood glucose levels often show completely different responses. The measures we have now do not properly evaluate the differences among such patients, and this results in a lack of efficacy. I think this is the first problem. The second problem lies in the evaluation of drugs. We have not sufficiently established the hierarchy of drug actions or the hierarchy in relation to forms of the disease. The study of Prof. Brownlee on oxidative stress provided clear-cut experimental results. We need to conduct that kind of study in an interdisciplinary, comprehensive, systemized way. Then, we will be able to say that things take place in such and such a sequence in a given group of patients, and thereby we could block this upstream reaction. Our science has not reached a point where we can use this strategy. We are not able to evaluate this hierarchy as yet. I think this is the second problem. Dr. Naihoko Ogata (Kansai Medical University): Thank you for your lecture covering a truly wide range of topics. Diabetes involves complicated interactions among various factors, such as NO reduction, oxidative stress, angiotensin, cytokines and VEGF. Is there a way to identify which is the main factor determining the condition of an individual patient? Dr. Yamashita: A problem at least lies in the study strategy. We need a clearer understanding of signal transduction in the cell on the molecular level. At present, we are looking at only crude changes. At the gene transcription level, for example, we should be able to see signals converging to a point and then spreading, in this way. Observed changes should be quite limited. If we can grasp these processes, we can say at least phenomenologically that a change in any factor, whether it is an elevation in VEGF or an elevation in PEDF, affects largely the same set of molecules, and the observed changes will be additions and subtractions among the effects of these factors. It is impossible at present to build a mathematical formula including all of these factors. Although microarray and proteome studies are heading in this direction, they are probably not sufficient. I speculate that future developments in the study of regulation at the gene expression level may be helpful. We have made much progress at the laboratory level, but there is a tremendous gap between laboratory findings and clinical application. If we can establish a method to evaluate these things, we may have a breakthrough. As for the study target, drugs regulating

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various gene expression levels are essentially ideal, because they act on the root cause of various changes. Phenomenologically, it is good to look at crude changes, such as generation of active oxygen species and its consequences, and such an approach enables us to draw schemes in a relatively simple way. But it has not led to clinical efficacy. I think the study of intracellular signal transduction is essential, although I have no evidence. Dr. Ogata: Thank you. What do you think about the clinical trials concerning the involvement of angiotensin II and platelet functions? Dr. Yamashita: I feel that clinical trials on angiotensin II and PKCß inhibitors are targeted at cases with severe progression. If these agents are used for cases in somewhat earlier stages and are combined with blood glucose regulation, I expect they would be effective in delaying the onset of symptoms. For example, aspirin and other drugs regulating platelet functions may be effective, if they are used for a long period, starting from early stages. Even if we do

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not have the right method to evaluate drugs, we can pick up effective drugs by using carefully designed methods of drug administration. In other words, we have to use the second best way to evaluate drug effects, such as clinical observation of the fundus, blood glucose control, blood pressure etc. Starting medication early is a promising possibility. But in this case, a problem is the very long time required for a clinical trial. We need about 10 years to evaluate the onset of retinopathy, and we need to examine a very large number of patients. Probably we cannot plan such a clinical trial because of this problem. We may need to develop a practical way of clinically evaluating drugs. Through approaches like this, I hope that we will be able to use existing drugs more effectively. Dr. Miyake: It is time to close this discussion. Thank you very much. As we have seen, the study of diabetic retinopathy is advancing steadily. I hope to see further developments in the near future. Thank you.

Question and Answer Sessions with Dr. Hidetoshi Yamashita

Question and Answer Ophthalmologica 2004;218(suppl 1):45–46 DOI: 10.1159/000079468

Question and Answer Sessions with Dr. René G. Mély

Tokyo

Chairman: Prof. Dr. Mitsuru Sawa (Department of Ophthalmology, Nihon University School of Medicine) Dr. Sawa: Any questions will be invited from the audience. Please do not hesitate to speak in Japanese. Dr. Osamu Katsumi (Tokyo): Thank you for the lecture. I practice in Tokyo and prescribe contact lenses. What kind of patients would you not prescribe this 30-day compliant lens for? Dr. Mély: First, I would not prescribe extended-wear lenses if the patient is not compliant. It is not always easy to say which patients are reliable and which are not. Noncompliance is a problem because patients begin to wear lenses for 2 or 3 months without changing them. And secondly, I would be very careful in cases of immune deficiency. Dr. Sawa: In a historical context, you showed us that the rate of extended lens wear differed between countries. For instance, in Sweden, the rate was high. But in Germany, the rate was about 4%, which is very low. What factors affected the difference between these two countries? Dr. Mély: This is difficult to say. One point is certain about Sweden: as in other Scandinavian countries, the first disposable extended-wear lenses were introduced very early in the eighties. The name of the lens was Danalens®, a precursor of the Acuvue® lens, and it was very popular in Scandinavia. But I think the most important point is the attitude of eye care professionals who recommend them or do not. Probably in Germany, and also in France, ophthalmologists have always been very cautious about recommending extended-wear lenses.

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Dr. Sawa: What is the percentage of 30-day extended wear lens users in Europe? You told us that there are about 800,000 users. Dr. Mély: There are no studies which give us exact data. We have only data on the sales number of lenses, which gives us an estimate of the number of lens wearers. But it is very difficult to know how many people are then wearing these lenses on an extended-wear basis or just on a daily-wear basis. So, I don’t have more precise data to give you. Dr. Sawa: We are having a party after this session. Dr. Mély will accept your individual questions at the party. Thank you very much.

Osaka

Chairman: Prof. Shigeru Kinoshita (Kyoto Prefectural University) Dr. Kinoshita: Thank you for the very interesting lecture. I am much intrigued because I myself have no experience in the therapeutic use of these lenses. Are there any questions from the audience? Dr. Hikaru Hamano (Osaka): Thank you very much for your very informative lecture. The results showed that high-Dk lenses (125 or 175 ! –9 10 ) performed almost the same as the control, and the oxygen pressure under the lens or under the cornea is less than 20 mm Hg. Do you think 20 mm Hg is enough for continuous or extended wear? Dr. Mély: This is a difficult question. I think you know more about oxygen transmissibility measurements than I do. I have only a clinical experience with these lenses and

have not performed any research about the minimum oxygen requirements of the cornea. I must say that I have not seen any oxygen-related problems with high-Dk lenses in my clinic, so I think a Dk/L of 175 ! 10 –9 is enough. Dr. Motozumi Itoi (Tokyo): I suspect that these lenses are associated with a somewhat higher occurrence of mechanical complications. With respect to giant papillary conjunctivitis (GPC), these lenses seem to induce a type of GPC that has not been observed with conventional soft lenses. So, I think there is a need for modifying lens design or hardness. What is your opinion? My second question is about keratitis due to MK infection. Different countries have different diagnostic criteria for a bacterial corneal infiltration and contact lensinduced peripheral ulceration. The reported high prevalence in Australia might be affected by the data from the group of Brian Holden. Do you think we can actually expect the reported low occurrence when we compare these silicone hydrogel lenses with daily-wear and monthly-wear contact lenses from other manufacturers? Dr. Mély: The answer to the first part of your question is that I have not seen any typical mechanically induced GPC case in my own series of patients. I must say, however, that I do not have a large experience on long-term wear of these lenses as most of my patients were fitted for therapeutic purposes. I am afraid I have not understood very well the second part of the question. Dr. Itoi: The concept of a bacterial corneal infiltration has not been widely understood in Japan. The literature from overseas in the last decade shows that this concept has been established gradually. In this sense, I’m concerned if we can directly compare current and past studies. I’d like to hear your opinion. Dr. Mély: I also have the feeling that a number of cases of so-called sterile infiltrations were referred to in past studies as bacterial keratitis. I must say however that it is quite difficult to demonstrate this retrospectively. We need more precise criteria to differentiate severe microbial keratitis from infiltrative events. Therefore in the research literature one has to look very precisely at the diagnostic criteria of keratitis utilized in order to compare conclusions from different studies. Dr. Itoi: Let me explain why I asked this question. In various statistics of eye disorders in Japan, the data reported that so-called corneal infiltration is considered to include many cases of contact-lens-induced peripheral ulceration. When we look at international statistics related to these silicone hydrogel lenses, the data include about 5% of such cases. I asked the question because I wanted to

46

Ophthalmologica 2004;218(suppl 1):45–46

know how we should compare the data from Japan and those from overseas. Dr. Wakako Iwasaki (Osaka City): Shortly ago, Dr. Itoi and I attended a meeting of contact lens specialists. My impression at the meeting was that these lenses tend to cause small scratches on the cornea due to poor finish of the edges. In addition, they may form crystalline deposition at about 2 mm from the lens edge. According to the data presented, these lenses are not suitable to smokers because the indoor air around smokers is contaminated and the lenses absorb contaminants in air during the processes of disinfection and oxygen intake. Could you elaborate on the reason why these lenses are not suitable to smokers? Dr. Mély: Smoking is obviously very unhealthy for all contact lens wearers. It has been proven that smoking is a risk factor for keratitis, but the mechanism is actually not known. I do not think it is related to crystalline deposition on the lens surface but I cannot give you an exact answer related to etiology. Dr. Kiichi Ueda (Shimonoseki City): My question is related to the question from Dr. Itoi. Could you provide some more information about GPC associated with these lenses? As a matter of fact, I have a patient who was fitted with silicone hydrogel soft contact lenses at a clinic overseas. This case developed severe GPC during continuous wear. Some doctors who participated in the clinical trial of these lenses commented that they seemed to cause a somewhat high incidence of GPC. If it were the case, what is your opinion about the problems of lens material, surface treatment and design? Dr. Mély: I don’t believe that the incidence is high. I think this form of GPC is related to a mechanical factor. This is due to the high modulus of the lenses, and maybe also to lens design. These are considerations important to improve in the future. Dr. Kinoshita: I have just a simple question for you. What do you think about the guidelines for the advantages of soft contact lenses? What team developed the guidelines? Dr. Mély: These guidelines were developed in Germany by the two major societies of ophthalmology in our country, the BVA and the DOG. Dr. Kinoshita: Thank you very much. It is time to end this session. Thank you for your attention.

Question and Answer Sessions with Dr. René G. Mély

The 16th CIBA Vision Symposium November 6, 2003, Osaka November 8, 2003, Tokyo

Proceedings

Guest Editors

Yasuo Tano, Osaka Yoshihisa Oguchi, Tokyo

Basel • Freiburg • Paris • London • New York • Bangalore • Bangkok • Singapore • Tokyo • Sydney

The current publication was made possible by an educational grant from CIBA Vision K.K. Professional Marketing Group Tennoz Central Tower 13F 2-2-24 Higashi-Shinagawa, Shinagawa-ku Tokyo 140-0002 (Japan)

S. Karger Medical and Scientific Publishers Basel • Freiburg • Paris • London New York • Bangalore • Bangkok Singapore • Tokyo • Sydney

Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.

All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center (see ‘General Information’). © Copyright 2004 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3–8055–7839–3

Vol. 218, Supplement 1, 2004

Contents

The 16th CIBA Vision Symposium 1 Organizing Committee Members Osaka/Tokyo 3 Opening Address

Lecture 1 5 Risk Profiles for Ageing Macular Disease de Jong, P.T.V.M. (Amsterdam)

Lecture 2 17 Pathogenesis of Diabetic Retinopathy and Strategy to Develop New

Therapeutic Modalities Yamashita, H. (Yamagata)

Lecture 3 33 Therapeutic and Cosmetic Indications of Lotrafilcon A Silicone Hydrogel

Extended-Wear Lenses Mély, R.G. (Saarlouis)

Question and Answer 39 Question and Answer Session with Dr. Paulus T.V.M. de Jong 42 Question and Answer Sessions with Dr. Hidetoshi Yamashita 45 Question and Answer Sessions with Dr. René G. Mély

© 2004 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/oph_issues

16th CIBA Vision Symposium

Organizing Committee Members – Osaka

Dr. Shigeru Kinoshita

Dr. Yozo Miyake

Dr. Akira Negi

Professor of Ophthalmology Kyoto Prefectural University of Medicine

Professor of Ophthalmology Nagoya University School of Medicine

Professor of Ophthalmology Kobe University Medical School

Dr. Yasuo Tano

Dr. Hisashi Tsukamoto

Professor of Ophthalmology Osaka University Medical School

Chairman of the Osaka Ophthalmologists Association

Organizing Committee Members – Tokyo

Dr. Kenji Kitahara

Dr. Koji Kurata

Dr. Yoshihisa Oguchi

Professor of Ophthalmology The Jikei University School of Medicine

Chairman of the Tokyo Association of Ophthalmologists

Professor of Ophthalmology School of Medicine, Keio University

Dr. Mitsuru Sawa

Dr. Makoto Tamai

Dr. Masahiko Usui

Professor of Ophthalmology Nihon University School of Medicine

Professor of Ophthalmology Tohoku University School of Medicine

Professor of Ophthalmology Tokyo Medical University

ABC Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

© 2004 S. Karger AG, Basel

Accessible online at: www.karger.com/oph

1

Ophthalmologica 2004;218(suppl 1):3

Opening Address

We are delighted to publish the proceedings of the 16th CIBA Vision Symposium, held in Osaka and Tokyo from November 6 to November 8, 2003. This publication is the fifth appearing as special issue of Ophthalmologica. We invited three lecturers who are international ophthalmologists or researchers in ophthalmology. They were selected by the executive committee of the CIBA Vision Symposium. As for the selection of topics, we always choose inspiring and timely themes which attract a large audience. This time we invited Prof. Paulus T.V.M. de Jong, an authority on ophthalmic epidemiology from the Netherlands, Prof. Hidetoshi Yamashita, a specialist in diabetic retinopathy, from Yamagata University, Japan, and Dr. René G. Mély, specialist in contact lenses, from Germany. Prof. de Jong explained recent findings on risk factors and the profile for ageing macular disease (age-related macular degeneration). Prof. Yamashita lectured about new therapeutic modalities of diabetic retinopathy. Dr. Mély talked about new contact lenses made of silicone hydrogel. These three topics are so up-to-date that we hope all readers will be interested in them. Yoshihisa Oguchi, MD

ABC

© 2004 S. Karger AG, Basel 0030–3755/04/2187–0003$21.00/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/oph

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